Antibody molecules to lag-3 and uses thereof

ABSTRACT

Antibody molecules that specifically bind to LAG-3 are disclosed. The anti-LAG-3 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/953,536, filed Mar. 14, 2014, U.S. Provisional Application No.62/059,690, filed Oct. 3, 2014, and U.S. Provisional Application No.62/094,889, filed Dec. 19, 2014, the contents of the aforementionedapplications are hereby incorporated by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 10, 2015, isnamed C2160-700110_SL.txt and is 252,850 bytes in size.

BACKGROUND

Lymphocyte Activation Gene-3, or LAG-3 (also known as CD223), is amember of the immunoglobulin supergene family, and is expressed onactivated T cells (Huard et al. (1994) Immunogenetics 39:213), NK cells(Triebel et al. (1990) J. Exp. Med. 171:1393-1405), regulatory T cells(Huang et al. (2004) Immunity 21:503-513; Camisaschi et al. (2010) JImmunol. 184:6545-6551; Gagliani et al. (2013) Nat Med 19:739-746), andplasmacytoid dendritic cells (DCs) (Workman et al. (2009) J Immunol182:1885-1891). LAG-3 is a membrane protein encoded by a gene located onchromosome 12, and is structurally and genetically related to CD4.

Similar to CD4, LAG-3 can interact with MHC class II molecules on thecell surface (Baixeras et al. (1992) J. Exp. Med. 176:327-337; Huard etal. (1996) Eur. J. Immunol. 26:1180-1186). It has been suggested thatthe direct binding of LAG-3 to MHC class II plays a role indown-regulating antigen-dependent stimulation of CD4⁺ T lymphocytes(Huard et al. (1994) Eur. J. Immunol. 24:3216-3221) and LAG-3 blockadehas also been shown to reinvigorate CD8⁺ lymphocytes in both tumor orself-antigen (Gross et al. (2007) J Clin Invest. 117:3383-3392) andviral models (Blackburn et al. (2009) Nat. Immunol. 10:29-37). Further,the intra-cytoplasmic region of LAG-3 can interact with LAP(LAG-3-associated protein), which is a signal transduction moleculeinvolved in the downregulation of the CD3/TCR activation pathway(Iouzalen et al. (2001) Eur. J. Immunol. 31:2885-2891). Moreover,CD4+CD25⁺ regulatory T cells (T_(reg)) have been shown to express LAG-3upon activation, which contributes to the suppressor activity of T_(reg)cells (Huang, C. et al. (2004) Immunity 21:503-513). LAG-3 can alsonegatively regulate T cell homeostasis by T_(reg) cells in both Tcell-dependent and independent mechanisms (Workman, C. J. and Vignali,D. A. (2005) J. Immunol. 174:688-695).

Given the importance of LAG-3 in downregulating an immune response, theneed exists for developing novel agents that modulate its activity toactivate the immune system. Such agents can be used, e.g., for cancerimmunotherapy and treatment of other conditions, such as chronicinfection.

SUMMARY

Disclosed herein are antibody molecules (e.g., humanized antibodymolecules) that bind to Lymphocyte Activation Gene-3 (LAG-3) with highaffinity and specificity. In one embodiment, the anti-LAG-3 antibodymolecules include a novel combination of framework regions (e.g., FW1,FW2, FW3 and/or FW4), e.g., novel combinations of a heavy chainframework regions and/or light chain framework regions. Nucleic acidmolecules encoding the antibody molecules, expression vectors, hostcells and methods for making the antibody molecules are also provided.Immunoconjugates, multi- or bispecific antibody molecules andpharmaceutical compositions comprising the antibody molecules are alsoprovided. The anti-LAG-3 antibody molecules disclosed herein can be used(alone or in combination with other agents or therapeutic modalities) totreat, prevent and/or diagnose cancerous disorders (e.g., solid andsoft-tissue tumors), as well as infectious diseases. Thus, compositionsand methods for detecting LAG-3, as well as methods for treating variousdisorders, including cancer and/or infectious diseases using theanti-LAG-3 antibody molecules are disclosed herein.

Accordingly, in one aspect, the invention features an antibody molecule(e.g., an isolated or recombinant antibody molecule) having one or moreof the following properties:

(i) binds to LAG-3, e.g., human LAG-3, with high affinity, e.g., with anaffinity constant of at least about 10⁷ M⁻¹, typically about 10⁸ M⁻¹,and more typically, about 10⁹ M⁻¹ to 10¹⁰ M⁻¹ or stronger;

(ii) binds to LAG-3, e.g., a LAG-3-CHO transfectant, with a K_(D) ofless than: 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, e.g., 1 to 3 nM (e.g., about1.92 nM or about 2.3 nM);

(iii) does not substantially bind to CD4;

(iv) inhibits binding of LAG-3 to a major histocompatibility (MHC) classII molecule, e.g., shows an IC₅₀ of about 1 to 20 nM, 5 to 15 nM, e.g.,5.5 nM;

(v) binds to the D1 domain of LAG-3 (e.g., human LAG-3), e.g., binds tothe D1 domain, but does not bind to the extra loop region of the D1domain;

(vi) modulates (e.g., stimulates, enhances, or restores) an immuneresponse, e.g., an antigen-specific T cell response or anti-tumorresponse;

(vii) binds specifically to an epitope on LAG-3, e.g., the same orsimilar epitope as the epitope recognized by murine monoclonal antibodyBAP050 or chimeric antibody BAP050-chi;

(viii) binds to a different epitope on LAG-3 than the one recognized byantibody BMS-986016;

(ix) shows the same or similar binding affinity or specificity, or both,as any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09,BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J.

(x) shows the same or similar binding affinity or specificity, or both,as an antibody molecule (e.g., an heavy chain variable region and lightchain variable region) described in Table 1;

(xi) shows the same or similar binding affinity or specificity, or both,as an antibody molecule (e.g., an heavy chain variable region and lightchain variable region) having an amino acid sequence shown in Table 1;

(xii) shows the same or similar binding affinity or specificity, orboth, as an antibody molecule (e.g., an heavy chain variable region andlight chain variable region) encoded by the nucleotide sequence shown inTable 1;

(xiii) inhibits, e.g., competitively inhibits, the binding of a secondantibody molecule to LAG-3, wherein the second antibody molecule is anantibody molecule described herein, e.g., an antibody molecule chosenfrom, e.g., any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J;

(xiv) binds the same or an overlapping epitope with a second antibodymolecule to LAG-3, wherein the second antibody molecule is an antibodymolecule described herein, e.g., an antibody molecule chosen from, e.g.,any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09,BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J;

(xv) competes for binding, and/or binds the same epitope, with a secondantibody molecule to LAG-3, e.g., as measured by a Biacore method, aFACS method, or both, wherein the second antibody molecule is anantibody molecule described herein, e.g., an antibody molecule chosenfrom, e.g., any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J;

(xvi) has one or more biological properties of an antibody moleculedescribed herein, e.g., an antibody molecule chosen from, e.g., any ofBAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05,BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15,BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20,huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J;

(xvii) has one or more pharmacokinetic properties of an antibodymolecule described herein, e.g., an antibody molecule chosen from, e.g.,any of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09,BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or

(xviii) inhibits one or more activities of LAG-3, e.g., results in oneor more of: an increase in antigen-dependent stimulation of CD4⁺ Tlymphocytes; an increase in T cell proliferation; an increase inexpression of an activation antigen, e.g., CD25; an increase inexpression of a cytokine, e.g., interferon-gamma (IFN-γ), interleukin-2(IL-2), or interleukin-4 (IL-4); an increase in expression of achemokine, e.g., CCL3, CCL4, or CCL5; a decrease in the suppressoractivity of T_(reg) cells; an increase in T cell homeostasis; anincrease in tumor infiltrating lymphocytes; or a decrease in immuneevasion by the cancerous cells.

As used herein, “huBAP050(Ser)” refers to a humanized BAP050 antibodymolecule, e.g., any of the humanized BAP050 antibody molecule describedherein, e.g., as described in Table 1, that has a Cys to Sersubstitution at position 84 of the heavy chain framework region 3(VHFW3). In some embodiments, the huBAP050(Ser) antibody molecule ischosen from BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser.

In some embodiments, the anti-LAG-3 antibody molecule binds to LAG-3with high affinity, e.g., with a dissociation equilibrium constant(K_(D)) that is about the same, or at least about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80% or 90% higher or lower than the K_(D) of a murine orchimeric anti-LAG-3 antibody molecule, e.g., a murine or chimericanti-LAG-3 antibody molecule described herein. In one embodiment, theanti-LAG-3 antibody molecule binds to LAG-3, e.g., a LAG-3-CHOtransfectant, with a K_(D) of less than: 5 nM, 4 nM, 3 nM, 2 nM, e.g., 1to 3 nM (e.g., about 1.92 nM or about 2.3 nM).

In some embodiments, the expression level of the anti-LAG-3 antibodymolecule is about the same, higher or lower, e.g., at least about 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10-fold higher or lower, than theexpression level of a murine or chimeric antibody molecule, e.g., amurine or chimeric anti-LAG-3 antibody molecule described herein. Insome embodiments, the antibody molecule is expressed in CHO cells.

In some embodiments, the anti-LAG-3 antibody molecule reduces one ormore LAG-3-associated activities with an IC₅₀ (concentration at 50%inhibition) that is about the same, higher or lower, e.g., at leastabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% higher or lower,than the IC₅₀ of a murine or chimeric anti-LAG-3 antibody molecule,e.g., a murine or chimeric anti-LAG-3 antibody molecule describedherein. In some embodiments, the LAG-3-associated activity is thebinding of an MHC class II molecule to LAG-3. In some embodiments, theLAG-3-associated activity is the binding of L-SECtin to LAG-3. In oneembodiment, the anti-LAG-3 antibody has an IC₅₀ of about 1 to 20 nM, 5to 15 nM, 5.5 nM (e.g., detected by inhibition of MHC class II orL-SECtin binding).

In some embodiments, the anti-LAG-3 antibody molecule has about the sameor improved stability, e.g., at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8,9 or 10-fold more stable in vivo or in vitro, than a murine or chimericanti-LAG-3 antibody molecule, e.g., a murine or chimeric anti-LAG-3antibody molecule described herein.

In one embodiment, the anti-LAG-3 antibody molecule is a humanizedantibody molecule and has a risk score based on T cell epitope analysisof 800 to 1200, 850 to 1150, 900 to 1100, 950 to 1050, or a risk scoreas described herein.

In another embodiment, the anti-LAG-3 antibody molecule comprises atleast one antigen-binding region, e.g., a variable region or anantigen-binding fragment thereof, from an antibody described herein,e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described inTable 1, or encoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences.

In yet another embodiment, the anti-LAG-3 antibody molecule comprises atleast one, two, three or four variable regions from an antibodydescribed herein, e.g., an antibody chosen from any of BAP050-hum01,BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser)(e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser),BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, orBAP050-Clone-J; or as described in Table 1, or encoded by the nucleotidesequence in Table 1; or a sequence substantially identical (e.g., atleast 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to anyof the aforesaid sequences. In one embodiment, the antibody moleculeincludes a substitution (e.g., a Cys to Ser substitution at position 84)in the heavy chain framework region 3 (VHFW3) (e.g., as shown in Tables1 and 2).

In yet another embodiment, the anti-LAG-3 antibody molecule comprises atleast one or two heavy chain variable regions from an antibody describedherein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described inTable 1, or encoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences.

In yet another embodiment, the anti-LAG-3 antibody molecule comprises atleast one or two light chain variable regions from an antibody describedherein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or as described inTable 1, or encoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences.

In yet another embodiment, the anti-LAG-3 antibody molecule includes aheavy chain constant region for an IgG4, e.g., a human IgG4. In oneembodiment, the human IgG4 includes a substitution at position 228(e.g., a Ser to Pro substitution). In still another embodiment, theanti-LAG-3 antibody molecule includes a heavy chain constant region foran IgG1, e.g., a human IgG1. In one embodiment, the human IgG1 includesa substitution at position 297 (e.g., an Asn to Ala substitution). Inone embodiment, the human IgG1 includes a substitution at position 265,a substitution at position 329, or both (e.g., an Asp to Alasubstitution at position 265 and/or a Pro to Ala substitution atposition 329). In one embodiment, the human IgG1 includes a substitutionat position 234, a substitution at position 235, or both (e.g., a Leu toAla substitution at position 234 and/or a Leu to Ala substitution atposition 235). In one embodiment, the heavy chain constant regioncomprises an amino sequence set forth in Table 3, or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) thereto.

In yet another embodiment, the anti-LAG-3 antibody molecule includes akappa light chain constant region, e.g., a human kappa light chainconstant region. In one embodiment, the light chain constant regioncomprises an amino sequence set forth in Table 3, or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) thereto.

In another embodiment, the anti-LAG-3 antibody molecule includes a heavychain constant region for an IgG4, e.g., a human IgG4, and a kappa lightchain constant region, e.g., a human kappa light chain constant region,e.g., a heavy and light chain constant region comprising an aminosequence set forth in Table 3, or a sequence substantially identical(e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higheridentical) thereto. In one embodiment, the constant region is a mutatedIgG4, e.g., a mutated human IgG4 (e.g., has a mutation at position 228(e.g., a S228P mutation). In yet another embodiment, the anti-LAG-3antibody molecule includes a heavy chain constant region for an IgG1,e.g., a human IgG1, and a kappa light chain constant region, e.g., ahuman kappa light chain constant region, e.g., a heavy and light chainconstant region comprising an amino sequence set forth in Table 3, or asequence substantially identical (e.g., at least 80%, 85%, 90%, 92%,95%, 97%, 98%, 99% or higher identical) thereto. In one embodiment, thehuman IgG1 includes a substitution at position 297 (e.g., an Asn to Alasubstitution). In one embodiment, the human IgG1 includes a substitutionat position 265, a substitution at position 329, or both (e.g., an Aspto Ala substitution at position 265 and/or a Pro to Ala substitution atposition 329). In one embodiment, the human IgG1 includes a substitutionat position 234, a substitution at position 235, or both (e.g., a Leu toAla substitution at position 234 and/or a Leu to Ala substitution atposition 235).

In another embodiment, the anti-LAG-3 antibody molecule includes a heavychain variable domain and a constant region, a light chain variabledomain and a constant region, or both, comprising the amino acidsequence of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09,BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1, orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences. Theanti-LAG-3 antibody molecule, optionally, comprises a leader sequencefrom a heavy chain, a light chain, or both, as shown in Table 4; or asequence substantially identical thereto.

In yet another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, or three complementarity determining regions (CDRs) froma heavy chain variable region of an antibody described herein, e.g., anantibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two, orthree CDRs shown in Table 1.

In one embodiment, the anti-LAG-3 antibody molecule includes at leastone, two or three CDRs (or collectively all of the CDRs) from a heavychain variable region comprising an amino acid sequence shown in Table1, or encoded by a nucleotide sequence shown in Table 1. In oneembodiment, one or more of the CDRs (or collectively all of the CDRs)have one, two, three, four, five, six or more changes, e.g., amino acidsubstitutions or deletions, relative to the amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1.

In yet another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, or three complementarity determining regions (CDRs) froma light chain variable region of an antibody described herein, e.g., anantibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two, orthree CDRs shown in Table 1.

In yet another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, or three CDRs (or collectively all of the CDRs) from alight chain variable region comprising an amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1. In oneembodiment, one or more of the CDRs (or collectively all of the CDRs)have one, two, three, four, five, six or more changes, e.g., amino acidsubstitutions or deletions, relative to the amino acid shown in Table 1,or encoded by a nucleotide sequence shown in Table 1. In anotherembodiment, the anti-LAG-3 antibody molecule includes at least one, two,three, four, five or six CDRs (or collectively all of the CDRs) from aheavy and light chain variable region comprising an amino acid shown inTable 1, or encoded by a nucleotide sequence shown in Table 1. In oneembodiment, one or more of the CDRs (or collectively all of the CDRs)have one, two, three, four, five, six or more changes, e.g., amino acidsubstitutions or deletions, relative to the amino acid shown in Table 1,or encoded by a nucleotide sequence shown in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two,three, four, five, or six CDRs shown in Table 1.

In another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, three, four, five or six CDRs (or collectively all ofthe CDRs) from a heavy and light chain variable region comprising anamino acid sequence shown in Table 1, or encoded by a nucleotidesequence shown in Table 1. In one embodiment, one or more of the CDRs(or collectively all of the CDRs) have one, two, three, four, five, sixor more changes, e.g., amino acid substitutions or deletions, relativeto the amino acid sequence shown in Table 1, or encoded by a nucleotidesequence shown in Table 1.

In one embodiment, the anti-LAG-3 antibody molecule includes all sixCDRs from an antibody described herein, e.g., an antibody chosen fromany of BAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04,BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09,BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14,BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1, orencoded by the nucleotide sequence in Table 1, or closely related CDRs,e.g., CDRs which are identical or which have at least one amino acidalteration, but not more than two, three or four alterations (e.g.,substitutions, deletions, or insertions, e.g., conservativesubstitutions) relative to one, two, three, four, five, or six CDRsshown in Table 1. In one embodiment, the anti-LAG-3 antibody moleculemay include any CDR described herein.

In one embodiment, the anti-LAG-3 antibody molecule includes at leastone, two or three CDRs according to Kabat (e.g., at least one, two, orthree CDRs according to the Kabat definition as set out in Table 1) froma heavy chain variable region of an antibody described herein, e.g., anantibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J, or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two, orthree CDRs according to Kabat shown in Table 1.

In one embodiment, the anti-LAG-3 antibody molecule includes at leastone, two or three CDRs according to Kabat (e.g., at least one, two, orthree CDRs according to the Kabat definition as set out in Table 1) froma light chain variable region of an antibody described herein, e.g., anantibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two, orthree CDRs according to Kabat shown in Table 1.

In yet another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, three, four, five, or six CDRs according to Kabat (e.g.,at least one, two, three, four, five, or six CDRs according to the Kabatdefinition as set out in Table 1) from the heavy and light chainvariable regions of an antibody described herein, e.g., an antibodychosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to at least one,two, three, four, five, or six CDRs according to Kabat et al. shown inTable 1. In one embodiment, the anti-LAG-3 antibody molecule may includeany CDR described herein.

In yet another embodiment, the anti-LAG-3 antibody molecule includes allsix CDRs according to Kabat (e.g., all six CDRs according to the Kabatdefinition as set out in Table 1) from the heavy and light chainvariable regions of an antibody described herein, e.g., an antibodychosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to all six CDRsaccording to Kabat et al. shown in Table 1. In one embodiment, theanti-LAG-3 antibody molecule may include any CDR described herein.

In another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two or three hypervariable loops (e.g., at least one, two, orthree hypervariable loops according to the Chothia definition as set outin Table 1) from a heavy chain variable region of an antibody describedherein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, according to Chothia(e.g., at least one, two, or three hypervariable loops according to theChothia definition as set out in Table 1); or encoded by the nucleotidesequence in Table 1; or a sequence substantially identical (e.g., atleast 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to anyof the aforesaid sequences; or which have at least one amino acidalteration, but not more than two, three or four alterations (e.g.,substitutions, deletions, or insertions, e.g., conservativesubstitutions) relative to one, two, or three hypervariable loopsaccording to Chothia shown in Table 1.

In another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two or three hypervariable loops according to Chothia (e.g.,at least one, two, or three CDRs according to the Chothia definition asset out in Table 1) from a light chain variable region of an antibodydescribed herein, e.g., an antibody chosen from any of BAP050-hum01,BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser)(e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser),BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, orBAP050-Clone-J; or encoded by the nucleotide sequence in Table 1; or asequence substantially identical (e.g., at least 80%, 85%, 90%, 92%,95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences; or which have at least one amino acid alteration, but notmore than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toone, two, or three hypervariable loops according to Chothia shown inTable 1.

In yet another embodiment, the anti-LAG-3 antibody molecule includes atleast one, two, three, four, five, or six hypervariable loops (e.g., atleast one, two, three, four, five, or six hypervariable loops accordingto the Chothia definition as set out in Table 1) from the heavy andlight chain variable regions of an antibody described herein, e.g., anantibody chosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J; or as described in Table 1; orencoded by the nucleotide sequence in Table 1; or at least the aminoacids from those hypervariable loops that contact LAG-3. In oneembodiment, the anti-LAG-3 antibody molecule includes at least one, two,three, four, five, or six Chothia hypervariable loops of Table 1.

In one embodiment, the anti-LAG-3 antibody molecule includes all sixhypervariable loops (e.g., all six hypervariable loops according to theChothia definition as set out in Table 1) of an antibody describedherein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, or closely relatedhypervariable loops, e.g., hypervariable loops which are identical orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to all sixhypervariable loops shown in Table 1. In one embodiment, the anti-LAG-3antibody molecule may include any hypervariable loop described herein.

In still another embodiment, the anti-LAG-3 antibody molecule includesat least one, two, or three hypervariable loops that have the samecanonical structures as the corresponding hypervariable loop of anantibody described herein, e.g., an antibody chosen from any ofBAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05,BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15,BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20,huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J, e.g., the same canonical structuresas at least loop 1 and/or loop 2 of the heavy and/or light chainvariable domains of an antibody described herein. See, e.g., Chothia etal., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol.Biol. 227:776-798 for descriptions of hypervariable loop canonicalstructures. These structures can be determined by inspection of thetables described in these references.

In certain embodiments, the anti-LAG-3 antibody molecule includes acombination of CDRs or hypervariable loops defined according to theKabat et al. and Chothia et al.

In one embodiment, the anti-LAG-3 antibody molecule includes at leastone, two or three CDRs or hypervariable loops from a heavy chainvariable region of an antibody described herein, e.g., an antibodychosen from any of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g., BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J, according to the Kabat and Chothiadefinition (e.g., at least one, two, or three CDRs or hypervariableloops according to the Kabat and Chothia definition as set out in Table1); or encoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences; orwhich have at least one amino acid alteration, but not more than two,three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two, orthree CDRs or hypervariable loops according to Kabat and/or Chothiashown in Table 1.

For example, the anti-LAG-3 antibody molecule can include VH CDR1according to Kabat et al. or VH hypervariable loop 1 according toChothia et al., or a combination thereof, e.g., as shown in Table 1. Inone embodiment, the combination of Kabat and Chothia CDR of VH CDR1comprises the amino acid sequence GFTLTNYGMN (SEQ ID NO: 286), or anamino acid sequence substantially identical thereto (e.g., having atleast one amino acid alteration, but not more than two, three or fouralterations (e.g., substitutions, deletions, or insertions, e.g.,conservative substitutions)). The anti-LAG-3 antibody molecule canfurther include, e.g., VH CDRs 2-3 according to Kabat et al. and VL CDRs1-3 according to Kabat et al., e.g., as shown in Table 1. Accordingly,in some embodiments, framework regions are defined based on acombination of CDRs defined according to Kabat et al. and hypervariableloops defined according to Chothia et al. For example, the anti-LAG-3antibody molecule can include VH FR1 defined based on VH hypervariableloop 1 according to Chothia et al. and VH FR2 defined based on VH CDRs1-2 according to Kabat et al., e.g., as shown in Table 1. The anti-LAG-3antibody molecule can further include, e.g., VH FRs 3-4 defined based onVH CDRs 2-3 according to Kabat et al. and VL FRs 1-4 defined based on VLCDRs 1-3 according to Kabat et al.

The anti-LAG-3 antibody molecule can contain any combination of CDRs orhypervariable loops according to the Kabat and Chothia definitions. Inone embodiment, the anti-LAG-3 antibody molecule includes at least one,two or three CDRs from a light chain variable region of an antibodydescribed herein, e.g., an antibody chosen from any of BAP050-hum01,BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser)(e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser),BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, orBAP050-Clone-J, according to the Kabat and Chothia definition (e.g., atleast one, two, or three CDRs according to the Kabat and Chothiadefinition as set out in Table 1).

In an embodiment, e.g., an embodiment comprising a variable region, CDR(e.g., CDR or Kabat CDR), or other sequence referred to herein, e.g., inTable 1, the antibody molecule is a monospecific antibody molecule, abispecifc antibody molecule, or is an antibody molecule that comprisesan antigen binding fragment of an antibody, e.g., a half antibody orantigen binding fragment of a half antibody. In certain embodiments, theantibody molecule is a bispecific antibody molecule having a firstbinding specificity for LAG-3 and a second binding specifity for PD-1,TIM-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5), PD-L1 or PD-L2.

In one embodiment, the anti-LAG-3 antibody includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12.

In another embodiment, the anti-LAG-3 antibody molecule includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15.

In one embodiment, the anti-LAG-3 antibody molecule comprises the VHCDR1amino acid sequence of SEQ ID NO: 1. In another embodiment, theanti-LAG-3 antibody molecule comprises the VHCDR1 amino acid sequence ofSEQ ID NO: 4. In yet another embodiment, the anti-LAG-3 antibodymolecule comprises the VHCDR1 amino acid sequence of SEQ ID NO: 286.

In one embodiment, the light or the heavy chain variable framework(e.g., the region encompassing at least FR1, FR2, FR3, and optionallyFR4) of the anti-LAG-3 antibody molecule can be chosen from: (a) a lightor heavy chain variable framework including at least 80%, 85%, 87% 90%,92%, 93%, 95%, 97%, 98%, or preferably 100% of the amino acid residuesfrom a human light or heavy chain variable framework, e.g., a light orheavy chain variable framework residue from a human mature antibody, ahuman germline sequence, or a human consensus sequence; (b) a light orheavy chain variable framework including from 20% to 80%, 40% to 60%,60% to 90%, or 70% to 95% of the amino acid residues from a human lightor heavy chain variable framework, e.g., a light or heavy chain variableframework residue from a human mature antibody, a human germlinesequence, or a human consensus sequence; (c) a non-human framework(e.g., a rodent framework); or (d) a non-human framework that has beenmodified, e.g., to remove antigenic or cytotoxic determinants, e.g.,deimmunized, or partially humanized. In one embodiment, the light orheavy chain variable framework region (particularly FR1, FR2 and/or FR3)includes a light or heavy chain variable framework sequence at least 70,75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical oridentical to the frameworks of a VL or VH segment of a human germlinegene.

In certain embodiments, the anti-LAG-3 antibody molecule comprises aheavy chain variable domain having at least one, two, three, four, five,six, seven, ten, fifteen, twenty or more changes, e.g., amino acidsubstitutions or deletions, from an amino acid sequence ofBAP050-chi-HC, e.g., the amino acid sequence of the FR region in theentire variable region, e.g., shown in Figures. 9A-9B, or SEQ ID NO: 20or 22. In one embodiment, the anti-LAG-3 antibody molecule comprises aheavy chain variable domain having one or more of: E at position 1, V atposition 2, A at position 9, V at position 11, A at position 16, S atposition 17, L at position 18, R at position 19, V at position 20, V orG at position 24, I at position 37, A or S at position 40, R or T atposition 41, S at position 42, Q or R at position 43, R at position 44,E at position 46, I or L at position 48, V at position 68, V or T atposition 69, I at position 70, A at position 72, D at position 73, K atposition 74, V or I at position 76, Y at position 80, W at position 83,C or S at position 84, S or T at position 85, A at position 88, E or Sat position 89, V or M at position 93, or Y at position 95 of amino acidsequence of BAP050-chi-HC, e.g., the amino acid sequence of the FR inthe entire variable region, e.g., shown in Figures. 9A-9B, or SEQ ID NO:20 or 22. In one embodiment, the antibody molecule includes asubstitution (e.g., a Cys to Ser substitution at position 84) in theheavy chain framework region 3 (VHFW3) (e.g., as shown in Table 2).

Alternatively, or in combination with the heavy chain substitutions ofBAP050-chi-HC described herein, the anti-LAG-3 antibody moleculecomprises a light chain variable domain having at least one, two, three,four, five, six, seven, ten, fifteen, twenty or more amino acid changes,e.g., amino acid substitutions or deletions, from an amino acid sequenceof BAP050-chi-LC, e.g., the amino acid sequence shown in Figures.10A-10B, or SEQ ID NO: 24 or 26. In one embodiment, the anti-LAG-3antibody molecule comprises a heavy chain variable domain having one ormore of: E or A at position 1, V at position 3, L at position 4, S atposition 7, P at position 8, A or L or D at position 9, T or F atposition 10, Q at position 11, P at position 12, V or L at position 13,T at position 14, V or P at position 15, K at position 16, Q or E atposition 17, T or P or K at position 18, A at position 19, S at position20, L at position 21, T at position 22, L at position 37, G at position41, K or Q at position 42, A or S at position 43, P at position 44, R orQ at position 45, L at position 46, I at position 58, P or D at position60, Y at position 67, E at position 70, F at position 71, T at position72, F at position 73, N at position 76, S or R at position 77, I atposition 78, Q at position 79, A or S or P at position 80, D at position81, A or F at position 83, Y or V at position 85, or F at position 87 ofthe amino acid sequence of BAP050-chi-LC, e.g., the amino acid sequenceshown in Figures. 10A-10B, or SEQ ID NO: 24 or 26.

In other embodiments, the anti-LAG-3 antibody molecule includes one,two, three, or four heavy chain framework regions (e.g., a VHFW aminoacid or nucleotide sequence shown in Table 2, or encoded by thenucleotide sequence shown in Table 2), or a sequence substantiallyidentical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% ormore identical thereto, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).In one embodiment, the antibody molecule includes a substitution (e.g.,a Cys to Ser substitution at position 84) in the heavy chain frameworkregion 3 (VHFW3) (e.g., as shown in Table 2).

In yet other embodiments, the anti-LAG-3 antibody molecule includes one,two, three, or four light chain framework regions (e.g., a VLFW aminoacid sequence shown in Table 2, or encoded by the nucleotide sequenceshown in Table 2), or a sequence substantially identical thereto (e.g.,a sequence at least about 85%, 90%, 95%, 99% or more identical thereto,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In other embodiments, the anti-LAG-3 antibody molecule includes one,two, three, or four heavy chain framework regions (e.g., a VHFW aminoacid sequence shown in Table 2, or encoded by the nucleotide sequenceshown in Table 2), or a sequence substantially identical thereto; andone, two, three, or four light chain framework regions (e.g., a VLFWamino acid sequence shown in Table 2, or encoded by the nucleotidesequence shown in Table 2), or a sequence substantially identicalthereto.

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework region 1 (VHFW1) of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum14, BAP050-hum15, BAP050-hum18, BAP050-hum19,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,BAP050-Clone-F, or BAP050-Clone-G (e.g., SEQ ID NO: 187). In someembodiments, the antibody molecule comprises the heavy chain frameworkregion 1 (VHFW1) of BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, or BAP050-hum20, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone J (e.g., SEQ ID NO:190). In some embodiments, the antibody molecule comprises the heavychain framework region 1 (VHFW1) of BAP050-hum16 (e.g., SEQ ID NO: 194).In some embodiments, the antibody molecule comprises the heavy chainframework region 1 (VHFW1) of BAP050-hum17 (e.g., SEQ ID NO: 196). Inother embodiments, the antibody molecule comprises a heavy chainframework region 1 (VHFW1) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework region 2 (VHFW2) of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum13, BAP050-hum17, BAP050-hum18, BAP050-hum19,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum13-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, BAP050-Clone-F,BAP050-Clone-G, or BAP050-Clone-J (e.g., SEQ ID NO: 198). In someembodiments, the antibody molecule comprises the heavy chain frameworkregion 2 (VHFW2) of BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum20, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum20-Ser, or BAP050-Clone-I(e.g., SEQ ID NO: 202). In some embodiments, the antibody moleculecomprises the heavy chain framework region 2 (VHFW2) of BAP050-hum14,BAP050-hum15, BAP050-hum14-Ser, or BAP050-hum15-Ser (e.g., SEQ ID NO:206). In some embodiments, the antibody molecule comprises the heavychain framework region 2 (VHFW2) of BAP050-hum16 (e.g., SEQ ID NO: 208).In other embodiments, the antibody molecule comprises a heavy chainframework region 2 (VHFW2) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework region 3 (VHFW3) of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum18, BAP050-hum19, orBAP050-hum20 (e.g., SEQ ID NO: 210). In some embodiments, the antibodymolecule comprises the heavy chain framework region 3 (VHFW3) ofBAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J (e.g., SEQ ID NO:212). In some embodiments, the antibody molecule comprises the heavychain framework region 3 (VHFW3) of BAP050-hum16 (e.g., SEQ ID NO: 217).In some embodiments, the antibody molecule comprises the heavy chainframework region 3 (VHFW3) of BAP050-hum17 (e.g., SEQ ID NO: 219). Inother embodiments, the antibody molecule comprises a heavy chainframework region 3 (VHFW3) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework region 4 (VHFW4) of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, or BAP050-hum20, BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J (e.g., SEQ ID NO: 221). In otherembodiments, the antibody molecule comprises a heavy chain frameworkregion 4 (VHFW4) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises thelight chain framework region 1 (VLFW1) of BAP050-hum01, BAP050-hum02,BAP050-hum04, BAP050-hum07, BAP050-hum09, BAP050-hum11, BAP050-hum13,BAP050-hum17, BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum04-Ser,BAP050-hum07-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum13-Ser,BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, orBAP050-Clone-J (e.g., SEQ ID NO: 226). In some embodiments, the antibodymolecule comprises the light chain framework region 1 (VLFW1) ofBAP050-hum03, BAP050-hum10, BAP050-hum14, BAP050-hum03-Ser,BAP050-hum10-Ser, or BAP050-hum14-Ser (e.g., SEQ ID NO: 230). In someembodiments, the antibody molecule comprises the light chain frameworkregion 1 (VLFW1) of BAP050-hum05 or BAP050-hum05-Ser (e.g., SEQ ID NO:232). In some embodiments, the antibody molecule comprises the lightchain framework region 1 (VLFW1) of BAP050-hum06, BAP050-hum20,BAP050-hum06-Ser, or BAP050-hum20-Ser (e.g., SEQ ID NO: 234). In someembodiments, the antibody molecule comprises the light chain frameworkregion 1 (VLFW1) of BAP050-hum08, BAP050-hum12, BAP050-hum15,BAP050-hum16, BAP050-hum19, BAP050-hum08-Ser, BAP050-hum12-Ser,BAP050-hum15-Ser, or BAP050-hum19-Ser (e.g., SEQ ID NO: 236). In someembodiments, the antibody molecule comprises the light chain frameworkregion 1 (VLFW1) of BAP050-hum18 or BAP050-hum18-Ser (e.g., SEQ ID NO:238). In other embodiments, the antibody molecule comprises a lightchain framework region 1 (VLFW1) having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises thelight chain framework region 2 (VLFW2) of BAP050-hum01, BAP050-hum02,BAP050-hum05, BAP050-hum09, BAP050-hum13, BAP050-hum17,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser,BAP050-hum13-Ser, BAP050-hum17-Ser, BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J (e.g., SEQ ID NO:240). In some embodiments, the antibody molecule comprises the lightchain framework region 2 (VLFW2) of BAP050-hum03, BAP050-hum06,BAP050-hum08, BAP050-hum10, BAP050-hum12, BAP050-hum14, BAP050-hum15,BAP050-hum16, BAP050-hum18, BAP050-hum19, BAP050-hum20,BAP050-hum03-Ser, BAP050-hum06-Ser, BAP050-hum08-Ser, BAP050-hum10-Ser,BAP050-hum12-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser (e.g., SEQ ID NO: 244). In someembodiments, the antibody molecule comprises the light chain frameworkregion 2 (VLFW2) of BAP050-hum04 or BAP050-hum04-Ser (e.g., SEQ ID NO:246). In some embodiments, the antibody molecule comprises the lightchain framework region 2 (VLFW2) of BAP050-hum07, BAP050-hum11,BAP050-hum07-Ser, or BAP050-hum11-Ser (e.g., SEQ ID NO: 248). In otherembodiments, the antibody molecule comprises a light chain frameworkregion 2 (VLFW2) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises thelight chain framework region 3 (VLFW3) of BAP050-hum01, BAP050-hum03,BAP050-hum05, BAP050-hum10, BAP050-hum14, BAP050-hum19,BAP050-hum01-Ser, BAP050-hum03-Ser, BAP050-hum05-Ser, BAP050-hum10-Ser,BAP050-hum14-Ser, BAP050-hum19-Ser, or BAP050-Clone-F (e.g., SEQ ID NO:252). In some embodiments, the antibody molecule comprises the lightchain framework region 3 (VLFW3) of BAP050-hum02, BAP050-hum09,BAP050-hum13, BAP050-hum02-Ser, BAP050-hum09-Ser, BAP050-hum13-Ser,BAP050-Clone-G, BAP050-Clone-H, or BAP050-Clone-J (e.g., SEQ ID NO:255). In some embodiments, the antibody molecule comprises the lightchain framework region 3 (VLFW3) of BAP050-hum04 or BAP050-hum04-Ser(e.g., SEQ ID NO: 259). In some embodiments, the antibody moleculecomprises the light chain framework region 3 (VLFW3) of BAP050-hum06,BAP050-hum07, BAP050-hum11, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum11-Ser, or BAP050-Clone-I (e.g., SEQ ID NO: 261). In someembodiments, the antibody molecule comprises the light chain frameworkregion 3 (VLFW3) of BAP050-hum08, BAP050-hum12, BAP050-hum15,BAP050-hum16, BAP050-hum18, BAP050-hum08-Ser, BAP050-hum12-Ser,BAP050-hum15-Ser, or BAP050-hum18-Ser (e.g., SEQ ID NO: 265). In someembodiments, the antibody molecule comprises the light chain frameworkregion 3 (VLFW3) of BAP050-hum17 (e.g., SEQ ID NO: 267). In someembodiments, the antibody molecule comprises the light chain frameworkregion 3 (VLFW3) of BAP050-hum20 or BAP050-hum20-Ser (e.g., SEQ ID NO:269). In other embodiments, the antibody molecule comprises a lightchain framework region 3 (VHLW3) having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises thelight chain framework region 4 (VLFW4) of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser,BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser,BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser,BAP050-hum20-Ser, BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J (e.g., SEQ ID NO: 271). In otherembodiments, the antibody molecule comprises a light chain frameworkregion 4 (VLFW4) having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum18, BAP050-hum19 (e.g., SEQ ID NO: 187 (VHFW1),SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)). In someembodiments, the antibody molecule comprises the heavy chain frameworkregions 1-3 of BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum20 (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2), andSEQ ID NO: 210 (VHFW3)). In some embodiments, the antibody moleculecomprises the heavy chain framework regions 1-3 of BAP050-hum13 (e.g.,SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210(VHFW3)). In some embodiments, the antibody molecule comprises the heavychain framework regions 1-3 of BAP050-hum14 or BAP050-hum15 (e.g., SEQID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3)).In some embodiments, the antibody molecule comprises the heavy chainframework regions 1-3 of BAP050-hum16 (e.g., SEQ ID NO: 194 (VHFW1), SEQID NO: 208 (VHFW2), and SEQ ID NO: 217 (VHFW3)). In some embodiments,the antibody molecule comprises the heavy chain framework regions 1-3 ofBAP050-hum17 (e.g., SEQ ID NO: 196 (VHFW1), SEQ ID NO: 198 (VHFW2), andSEQ ID NO: 219 (VHFW3)). In some embodiments, the antibody moleculecomprises the heavy chain framework regions 1-3 of BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser,BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, BAP050-Clone-F, or BAP050-Clone-G (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)). Insome embodiments, the antibody molecule comprises the heavy chainframework regions 1-3 of BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum20-Ser, BAP050-Clone-H, orBAP050-Clone I (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2),and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody moleculecomprises the heavy chain framework regions 1-3 of BAP050-hum13-Ser orBAP050-Clone-J (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2),and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody moleculecomprises the heavy chain framework regions 1-3 of BAP050-hum14-Ser orBAP050-hum15-Ser (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 206 (VHFW2),and SEQ ID NO: 212 (VHFW3)). In some embodiments, the antibody moleculefurther comprises the heavy chain framework region 4 of BAP050-hum01,BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser,BAP050-hum11-Ser, BAP050-hum13-Ser, BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J (e.g., SEQ ID NO:221). In other embodiments, the antibody molecule comprises a heavychain framework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum01, BAP050-hum01-Ser, orBAP050-Clone-F (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2),and SEQ ID NO: 252 (VLFW3)). In some embodiments, the antibody moleculecomprises the light chain framework regions 1-3 of BAP050-hum02,BAP050-hum09, BAP050-hum13, BAP050-hum02-Ser, BAP050-hum09-Ser,BAP050-hum13-Ser, BAP050-Clone-G, BAP050-Clone-H, or BAP050-Clone-J(e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO:255 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum03, BAP050-hum10,BAP050-hum14, BAP050-hum03-Ser, BAP050-hum10-Ser, or BAP050-hum14-Ser(e.g., SEQ ID NO: 230 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO:252 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum04 or BAP050-hum04-Ser(e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 246 (VLFW2), and SEQ ID NO:259 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum05 or BAP050-hum05-Ser(e.g., SEQ ID NO: 232 (VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO:252 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum06 or BAP050-hum06-Ser(e.g., SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO:261 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum07, BAP050-hum11,BAP050-hum07-Ser, BAP050-hum11-Ser, or BAP050-Clone-I (e.g., SEQ ID NO:226 (VLFW1), SEQ ID NO: 248 (VLFW2), and SEQ ID NO: 261 (VLFW3)). Insome embodiments, the antibody molecule comprises the light chainframework regions 1-3 of BAP050-hum08, BAP050-hum12, BAP050-hum15,BAP050-hum16, BAP050-hum08-Ser, BAP050-hum12-Ser, or BAP050-hum15-Ser(e.g., SEQ ID NO: 236 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO:265 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP050-hum17 (e.g., SEQ ID NO: 226(VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO: 267 (VLFW3)). In someembodiments, the antibody molecule comprises the light chain frameworkregions 1-3 of BAP050-hum18 or BAP050-hum18-Ser (e.g., SEQ ID NO: 238(VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). In someembodiments, the antibody molecule comprises the light chain frameworkregions 1-3 of BAP050-hum19 or BAP050-hum19-Ser (e.g., SEQ ID NO: 236(VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3)). In someembodiments, the antibody molecule comprises the light chain frameworkregions 1-3 of BAP050-hum20 or BAP050-hum20-Ser (e.g., SEQ ID NO: 234(VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 269 (VLFW3)). In someembodiments, the antibody molecule further comprises the heavy chainframework region 4 of BAP050-hum01, BAP050-hum02, BAP050-hum03,BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07, BAP050-hum08,BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12, BAP050-hum13,BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17, BAP050-hum18,BAP050-hum19, BAP050-hum20, BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, BAP050-hum20-Ser,BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, orBAP050-Clone-J (e.g., SEQ ID NO: 271). In other embodiments, theantibody molecule comprises a light chain framework region having asequence, or encoded by a sequence, substantially identical (e.g., asequence at least about 85%, 90%, 95%, 99% or more identical) to any ofthe aforesaid sequences, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum01 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum01-Ser or BAP050-Clone-F(e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO:212 (VHFW3)); and the light chain framework regions 1-3 of BAP050-hum01,BAP050-hum01-Ser, or BAP050-Clone-F (e.g., SEQ ID NO: 226 (VLFW1), SEQID NO: 240 (VLFW2), and SEQ ID NO: 252 (VLFW3)). In other embodiments,the antibody molecule comprises a heavy chain and a light chainframework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum02 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum02-Ser or BAP050-Clone-G(e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO:212 (VHFW3)); and the light chain framework regions 1-3 of BAP050-hum02,BAP050-hum02-Ser, or BAP050-Clone-G (e.g., SEQ ID NO: 226 (VLFW1), SEQID NO: 240 (VLFW2), and SEQ ID NO: 255 (VLFW3)). In other embodiments,the antibody molecule comprises a heavy chain and a light chainframework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum03 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum03-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum03 (e.g., SEQ ID NO:230 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum04 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum04-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum04 (e.g., SEQ ID NO:226 (VLFW1), SEQ ID NO: 246 (VLFW2), and SEQ ID NO: 259 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum05 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)) orBAP050-hum05-Ser (e.g., SEQ ID NO: 187 (VHFW1), SEQ ID NO: 198 (VHFW2),and SEQ ID NO: 212 (VHFW3)); and the light chain framework regions 1-3of BAP050-hum05 or BAP050-hum05-Ser (e.g., SEQ ID NO: 232 (VLFW1), SEQID NO: 240 (VLFW2), and SEQ ID NO: 252 (VLFW3)). In other embodiments,the antibody molecule comprises a heavy chain and a light chainframework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum06 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum06-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum06 (e.g., SEQ ID NO:234 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 261 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum07 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum07-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum07 (e.g., SEQ ID NO:226 (VLFW1), SEQ ID NO: 248 (VLFW2), and SEQ ID NO: 261 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum08 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum08-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum08 (e.g., SEQ ID NO:236 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum09 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3)), orBAP050-hum09-Ser or BAP050-Clone-H (e.g., SEQ ID NO: 190 (VHFW1), SEQ IDNO: 202 (VHFW2), and SEQ ID NO: 212 (VHFW3)); and the light chainframework regions 1-3 of BAP050-hum09, BAP050-hum09-Ser, orBAP050-Clone-H (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 240 (VLFW2),and SEQ ID NO: 255 (VLFW3)). In other embodiments, the antibody moleculecomprises a heavy chain and a light chain framework region having asequence, or encoded by a sequence, substantially identical (e.g., asequence at least about 85%, 90%, 95%, 99% or more identical) to any ofthe aforesaid sequences, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum10 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum10-Ser (e.g., SEQ ID NO:190 (VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum10 (e.g., SEQ ID NO:230 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum11 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3)), orBAP050-hum11-Ser, or BAP050-Clone-I (e.g., SEQ ID NO: 190 (VHFW1), SEQID NO: 202 (VHFW2), and SEQ ID NO: 212 (VHFW3)); and the light chainframework regions 1-3 of BAP050-hum11, BAP050-hum11-Ser, orBAP050-Clone-I (e.g., SEQ ID NO: 226 (VLFW1), SEQ ID NO: 248 (VLFW2),and SEQ ID NO: 261 (VLFW3)). In other embodiments, the antibody moleculecomprises a heavy chain and a light chain framework region having asequence, or encoded by a sequence, substantially identical (e.g., asequence at least about 85%, 90%, 95%, 99% or more identical) to any ofthe aforesaid sequences, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum12 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3)) orBAP050-hum12-Ser (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2),and SEQ ID NO: 212 (VHFW3)); and the light chain framework regions 1-3of BAP050-hum12 or BAP050-hum12-Ser (e.g., SEQ ID NO: 236 (VLFW1), SEQID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). In other embodiments,the antibody molecule comprises a heavy chain and a light chainframework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum13 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum13-Ser or BAP050-Clone-J(e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO:212 (VHFW3)); and the light chain framework regions 1-3 of BAP050-hum13,BAP050-hum13-Ser, or BAP050-Clone-J (e.g., SEQ ID NO: 226 (VLFW1), SEQID NO: 240 (VLFW2), and SEQ ID NO: 255 (VLFW3)). In other embodiments,the antibody molecule comprises a heavy chain and a light chainframework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum14 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum14-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum14 (e.g., SEQ ID NO:230 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum15 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum15-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 206 (VHFW2), and SEQ ID NO: 210 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum15 (e.g., SEQ ID NO:236 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum16 (e.g., SEQ ID NO: 194(VHFW1), SEQ ID NO: 208 (VHFW2), and SEQ ID NO: 217 (VHFW3)); and thelight chain framework regions 1-3 of BAP050-hum16 (e.g., SEQ ID NO: 236(VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). In otherembodiments, the antibody molecule comprises a heavy chain and a lightchain framework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum17 (e.g., SEQ ID NO: 196(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 219 (VHFW3)); and thelight chain framework regions 1-3 of BAP050-hum17 (e.g., SEQ ID NO: 226(VLFW1), SEQ ID NO: 240 (VLFW2), and SEQ ID NO: 267 (VLFW3)). In otherembodiments, the antibody molecule comprises a heavy chain and a lightchain framework region having a sequence, or encoded by a sequence,substantially identical (e.g., a sequence at least about 85%, 90%, 95%,99% or more identical) to any of the aforesaid sequences, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum18 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum18-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum18 (e.g., SEQ ID NO:238 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 265 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum19 (e.g., SEQ ID NO: 187(VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 210 (VHFW3)), or theheavy chain framework regions 1-3 of BAP050-hum18-Ser (e.g., SEQ ID NO:187 (VHFW1), SEQ ID NO: 198 (VHFW2), and SEQ ID NO: 212 (VHFW3)); andthe light chain framework regions 1-3 of BAP050-hum19 (e.g., SEQ ID NO:236 (VLFW1), SEQ ID NO: 244 (VLFW2), and SEQ ID NO: 252 (VLFW3)). Inother embodiments, the antibody molecule comprises a heavy chain and alight chain framework region having a sequence, or encoded by asequence, substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences,and/or having one, two, three or more substitutions, insertions ordeletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises theheavy chain framework regions 1-3 of BAP050-hum20 (e.g., SEQ ID NO: 190(VHFW1), SEQ ID NO: 202 (VHFW2), and SEQ ID NO: 210 (VHFW3)), orBAP050-hum20-Ser (e.g., SEQ ID NO: 190 (VHFW1), SEQ ID NO: 202 (VHFW2),and SEQ ID NO: 212 (VHFW3)); and the light chain framework regions 1-3of BAP050-hum20 (e.g., SEQ ID NO: 234 (VLFW1), SEQ ID NO: 244 (VLFW2),and SEQ ID NO: 269 (VLFW3)). In other embodiments, the antibody moleculecomprises a heavy chain and a light chain framework region having asequence, or encoded by a sequence, substantially identical (e.g., asequence at least about 85%, 90%, 95%, 99% or more identical) to any ofthe aforesaid sequences, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).

In some embodiments, the anti-LAG-3 antibody molecule comprises a heavychain framework region having a combination of framework regions FW1,FW2 and FW3 as shown in Figures. 4 or 6. In other embodiment, antibodymolecule comprises a light chain framework region having a combinationof framework regions FW1, FW2 and FW3 as shown in Figures. 4 or 6. Inyet other embodiments, the antibody molecule comprises a heavy chainframework region having a combination of framework regions FW1, FW2 andFW3 as shown in Figures. 4 or 6, and a light chain framework regionhaving a combination of framework regions FW1, FW2 and FW3 as shown inFigures. 4 or 6.

In one embodiment, the heavy or light chain variable domain, or both, ofthe of the anti-LAG-3 antibody molecule includes an amino acid sequence,which is substantially identical to an amino acid disclosed herein,e.g., at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% orhigher identical to a variable region of an antibody described herein,e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser), BAP050-Clone-F,BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or which differs at least 1 or 5 residues, but less than 40, 30, 20, or10 residues, from a variable region of an antibody described herein.

In one embodiment, the heavy or light chain variable region, or both, ofthe of the anti-LAG-3 antibody molecule includes an amino acid sequenceencoded by a nucleic acid sequence described herein or a nucleic acidthat hybridizes to a nucleic acid sequence described herein (e.g., aspecific nucleic acid sequence or a nucleic acid sequence that encodesan amino acid sequence described herein, e.g., as shown in Tables 1 and2) or its complement, e.g., under low stringency, medium stringency, orhigh stringency, or other hybridization condition described herein.

In another embodiment, the anti-LAG-3 antibody molecule comprises atleast one, two, three, or four antigen-binding regions, e.g., variableregions, having an amino acid sequence as set forth in Table 1, or asequence substantially identical thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, or which differs byno more than 1, 2, 5, 10, or 15 amino acid residues from the sequencesshown in Table 1). In another embodiment, the anti-LAG-3 antibodymolecule includes a VH and/or VL domain encoded by a nucleic acid havinga nucleotide sequence as set forth in Table 1, or a sequencesubstantially identical thereto (e.g., a sequence at least about 70%,75%, 85%, 90%, 95%, 99% or more identical thereto, or which differs byno more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown inTable 1).

In yet another embodiment, the anti-LAG-3 antibody molecule comprises atleast one, two, or three CDRs from a heavy chain variable region havingan amino acid sequence as set forth in Table 1, or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or having one, two, threeor more substitutions, insertions or deletions, e.g., conservedsubstitutions). In yet another embodiment, the anti-LAG-3 antibodymolecule comprises at least one, two, or three CDRs from a light chainvariable region having an amino acid sequence as set forth in Table 1,or a sequence substantially homologous thereto (e.g., a sequence atleast about 85%, 90%, 95%, 99% or more identical thereto, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions). In yet another embodiment, the anti-LAG-3antibody molecule comprises at least one, two, three, four, five or sixCDRs from heavy and light chain variable regions having an amino acidsequence as set forth in Table 1), or a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).In one embodiment, at least one, two, three, four, five or six CDR isdefined according to Kabat, e.g., as shown in Table 1. In anotherembodiment, at least one, two, three, four, five or six CDR is definedaccording to Chothia, e.g., as shown in Table 1.

In one embodiment, the anti-LAG-3 antibody molecule comprises at leastone, two, or three CDRs and/or hypervariable loops from a heavy chainvariable region having an amino acid sequence of an antibody describedherein, e.g., an antibody chosen from any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser), BAP050-Clone-F,BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, assummarized in Table 1, or a sequence substantially identical thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions). In another embodiment, theanti-LAG-3 antibody molecule comprises at least one, two, or three CDRsfrom a light chain variable region having an amino acid sequence of anantibody described herein, e.g., an antibody chosen from any ofBAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05,BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15,BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20,huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum05-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser), BAP050-Clone-F, BAP050-Clone-G, BAP050-Clone-H,BAP050-Clone-I, or BAP050-Clone-J, as summarized in Table 1, or asequence substantially identical thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, and/or having one,two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions). In one embodiment, the anti-LAG-3 antibodymolecule comprises all six CDRs and/or hypervariable loops describedherein, e.g., described in Table 1.

In one embodiment, the anti-LAG-3 antibody molecule has a variableregion that is identical in sequence, or which differs by 1, 2, 3, or 4amino acids from a variable region described herein (e.g., an FR regiondisclosed herein).

In one embodiment, the anti-LAG-3 antibody molecule is a full antibodyor fragment thereof (e.g., a Fab, F(ab′)₂, Fv, or a single chain Fvfragment (scFv)). In certain embodiments, the anti-LAG-3 antibodymolecule is a monoclonal antibody or an antibody with singlespecificity. The anti-LAG-3 antibody molecule can also be a humanized,chimeric, camelid, shark, or in vitro-generated antibody molecules. Inone embodiment, the anti-LAG-3 antibody molecule thereof is a humanizedantibody molecule. The heavy and light chains of the anti-LAG-3 antibodymolecule can be full-length (e.g., an antibody can include at least one,and preferably two, complete heavy chains, and at least one, andpreferably two, complete light chains) or can include an antigen-bindingfragment (e.g., a Fab, F(ab′)₂, Fv, a single chain Fv fragment, a singledomain antibody, a diabody (dAb), a bivalent or bispecific antibody orfragment thereof, a single domain variant thereof, or a camelidantibody).

In certain embodiments, the anti-LAG-3 antibody molecule is in the formof a bispecific or a multispecific antibody molecule. In one embodiment,the bispecific antibody molecule has a first binding specificity forLAG-3 and a second binding specifity for PD-1, TIM-3, CEACAM (e.g.,CEACAM-1 and/or CEACAM-5), PD-L1 or PD-L2. In one embodiment, thebispecific antibody molecule binds to LAG-3 and PD-1. In anotherembodiment, the bispecific antibody molecule binds to LAG-3 and TIM-3.In another embodiment, the bispecific antibody molecule binds to LAG-3and CEACAM (e.g., CEACAM-1 and/or CEACAM-5). In another embodiment, thebispecific antibody molecule binds to LAG-3 and CEACAM-1. In yet anotherembodiment, the bispecific antibody molecule binds to LAG-3 andCEACAM-5. In another embodiment, the bispecific antibody molecule bindsto LAG-3 and PD-L1. In yet another embodiment, the bispecific antibodymolecule binds to LAG-3 and PD-L2. Any combination of the aforesaidmolecules can be made in a multispecific antibody molecule, e.g., atrispecific antibody that includes a first binding specificity to LAG-3,and a second and third binding specificity to one or more of: PD-1,TIM-3, CEACAM (e.g., CEACAM-1 or CEACAM-5), PD-L1 or PD-L2.

In other embodiments, the anti-LAG-3 antibody molecule is used incombination with a bispecific molecule comprising one or more of: PD-1,TIM-3, CEACAM (e.g., CEACAM-1 or CEACAM-5), PD-L1 or PD-L2. In oneembodiment, the bispecific antibody molecule used in combination bindsto CEACAM (e.g., CEACAM-1 and/or CEACAM-5) and PD-1. In anotherembodiment, the bispecific antibody molecule used in combination bindsto CEACAM (e.g., CEACAM-1 and/or CEACAM-5) and TIM-3. In anotherembodiment, the bispecific antibody molecule used in combination bindsto PD-1 and TIM-3.

In yet other embodiments, the anti-LAG-3 antibody molecule has a heavychain constant region (Fc) chosen from, e.g., the heavy chain constantregions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE;particularly, chosen from, e.g., the heavy chain constant regions ofIgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constantregion of IgG, IgG2 or IgG4 (e.g., human IgG, IgG2 or IgG4). In oneembodiment, the heavy chain constant region is human IgG1 or human IgG4.In another embodiment, the anti-LAG-3 antibody molecule has a lightchain constant region chosen from, e.g., the light chain constantregions of kappa or lambda, preferably kappa (e.g., human kappa). In oneembodiment, the constant region is altered, e.g., mutated, to modify theproperties of the anti-LAG-3 antibody molecule (e.g., to increase ordecrease one or more of: Fc receptor binding, antibody glycosylation,the number of cysteine residues, effector cell function, or complementfunction). For example, the constant region is mutated at positions 296(M to Y), 298 (S to T), 300 (T to E), 477 (H to K) and 478 (N to F) toalter Fc receptor binding (e.g., the mutated positions correspond topositions 132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314(N to F) of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S toT), 139 (T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216,217 or 218). In another embodiment, the heavy chain constant region ofan IgG4, e.g., a human IgG4, is mutated at position 228 (e.g., S to P),e.g., as shown in Table 3. In certain embodiments, the anti-LAG-3antibody molecules comprises a human IgG4 mutated at position 228 (e.g.,S to P), e.g., as shown in Table 3; and a kappa light chain constantregion, e.g., as shown in Table 3. In still another embodiment, theheavy chain constant region of an IgG1, e.g., a human IgG1, is mutatedat one or more of position 297 (e.g., N to A), position 265 (e.g., D toA), position 329 (e.g., P to A), position 234 (e.g., L to A), orposition 235 (e.g., L to A), e.g., as shown in Table 3. In certainembodiments, the anti-LAG-3 antibody molecules comprises a human IgG1mutated at one or more of the aforesaid positions, e.g., as shown inTable 3; and a kappa light chain constant region, e.g., as shown inTable 3.

In one embodiment, the anti-LAG-3 antibody molecule is isolated orrecombinant.

In one embodiment, the anti-LAG-3 antibody molecule is a humanizedantibody molecule.

In one embodiment, the anti-LAG-3 antibody molecule has a risk scorebased on T cell epitope analysis of less than 1200, 1150, 1100, 1050,1000, 950, 900, 850, or 800.

In one embodiment, the anti-LAG-3 antibody molecule is a humanizedantibody molecule and has a risk score based on T cell epitope analysisof 800 to 1200, 850 to 1150, 900 to 1100, 950 to 1050, or a risk scoreas described herein.

The invention also features a nucleic acid molecule that comprises oneor more nucleotide sequences that encode heavy and light chain variableregions, CDRs, hypervariable loops, and/or framework regions of theanti-LAG-3 antibody molecules, as described herein. In certainembodiments, the nucleotide sequence that encodes the anti-LAG-3antibody molecule is codon optimized. For example, the inventionfeatures a first and second nucleic acid encoding heavy and light chainvariable regions, respectively, of an anti-LAG-3 antibody moleculechosen from one or more of, e.g., any of BAP050-hum01, BAP050-hum02,BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06, BAP050-hum07,BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11, BAP050-hum12,BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16, BAP050-hum17,BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser) (e.g.,BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser, BAP050-hum04-Ser,BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser, BAP050-hum08-Ser,BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser,BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser, BAP050-hum18-Ser,BAP050-hum19-Ser, or BAP050-hum20-Ser), BAP050-Clone-F, BAP050-Clone-G,BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J, as summarized inTable 1, or a sequence substantially identical thereto. For example, thenucleic acid can comprise a nucleotide sequence as set forth in Tables 1and 2, or a sequence substantially identical thereto (e.g., a sequenceat least about 85%, 90%, 95%, 99% or more identical thereto, or whichdiffers by no more than 3, 6, 15, 30, or 45 nucleotides from thesequences shown in Tables 1 and 2.

In other embodiments, the nucleic acid molecule comprises a nucleotidesequence that encodes a heavy chain variable domain and a heavy chainconstant region comprising the amino acid sequence of BAP050-Clone-F,BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

In other embodiments, the nucleic acid comprises a nucleotide sequencethat encodes a light chain variable domain and/or a light chain constantregion comprising the amino acid sequence of BAP050-Clone-F,BAP050-Clone-G, BAP050-Clone-H, BAP050-Clone-I, or BAP050-Clone-J; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

The aforesaid nucleotide sequences encoding the anti-LAG-3 heavy andlight chain variable domain and constant regions can be present in aseparate nucleic acid molecule, or in the same nucleic acid molecule. Incertain embodiments, the nucleic acid molecules comprise a nucleotidesequence encoding a leader sequence, e.g., a leader sequence as shown inTable 4, or a sequence substantially identical thereto.

In certain embodiments, the nucleic acid molecule comprise a nucleotidesequence encoding at least one, two, or three CDRs or hypervariableloops, from a heavy chain variable region having an amino acid sequenceas set forth in Table 1, or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions).

In another embodiment, the nucleic acid molecule comprise a nucleotidesequence encoding at least one, two, or three CDRs or hypervariableloops, from a light chain variable region having an amino acid sequenceas set forth in Table 1, or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions).

In yet another embodiment, the nucleic acid molecule can comprise anucleotide sequence encoding at least one, two, three, four, five, orsix CDRs or hypervariable loops, from heavy and light chain variableregions having an amino acid sequence as set forth in Table 1, or asequence substantially homologous thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, and/or having one,two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In one embodiment, the nucleic acid molecule includes a nucleotidesequence encoding an anti-LAG-3 antibody molecule that includes asubstitution (e.g., a Cys to Ser substitution at position 84) in theheavy chain framework region 3 (VHFW3) (e.g., as shown in Tables 1 and2).

In another embodiment, the nucleic acid molecule includes one or moreheavy chain framework region (e.g., any of VHFW1 (type a), VHFW1 (typeb), VHFW1 (type c), VHFW1 (type d), VHFW2 (type a), VHFW2 (type b),VHFW2 (type c), VHFW2 (type d), VHFW3 (type a), VHFW3 (type a′), VHFW3(type b), VHFW3 (type c), or VHFW4, or any combination thereof, e.g., aframework combination as described herein) for any of BAP050-hum01,BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05, BAP050-hum06,BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10, BAP050-hum11,BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15, BAP050-hum16,BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20, huBAP050(Ser)(e.g., BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum03-Ser,BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser, BAP050-hum07-Ser,BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser, BAP050-hum15-Ser,BAP050-hum18-Ser, BAP050-hum19-Ser, or BAP050-hum20-Ser),BAP049-Clone-F, BAP049-Clone-G, BAP049-Clone-H, BAP049-Clone-I, orBAP049-Clone-J, as summarized in Table 1 and 2, or a sequencesubstantially identical thereto. For example, the nucleic acid moleculecan comprise a nucleotide sequence as set forth in Tables 1 and 2, or asequence substantially identical thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, or which differs byno more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown inTables 1 and 2).

In another embodiment, the nucleic acid molecule includes one or morelight chain framework region (e.g., any of VLFW1 (type a), VLFW1 (typeb), VLFW1 (type c), VLFW1 (type d), VLFW1 (type e), VLFW1 (type f),VLFW2 (type a), VLFW2 (type b), VLFW2 (type c), VLFW2 (type d), VLFW3(type a), VLFW3 (type b), VLFW3 (type c), VLFW3 (type d), VLFW3 (typee), VLFW3 (type f), VLFW3 (type g), or VLFW4, or any combinationthereof, e.g., a framework combination as described herein) for any ofBAP050-hum01, BAP050-hum02, BAP050-hum03, BAP050-hum04, BAP050-hum05,BAP050-hum06, BAP050-hum07, BAP050-hum08, BAP050-hum09, BAP050-hum10,BAP050-hum11, BAP050-hum12, BAP050-hum13, BAP050-hum14, BAP050-hum15,BAP050-hum16, BAP050-hum17, BAP050-hum18, BAP050-hum19, BAP050-hum20,huBAP050(Ser) (e.g., BAP050-hum01-Ser, BAP050-hum02-Ser,BAP050-hum03-Ser, BAP050-hum04-Ser, BAP050-hum05-Ser, BAP050-hum06-Ser,BAP050-hum07-Ser, BAP050-hum08-Ser, BAP050-hum09-Ser, BAP050-hum10-Ser,BAP050-hum11-Ser, BAP050-hum12-Ser, BAP050-hum13-Ser, BAP050-hum14-Ser,BAP050-hum15-Ser, BAP050-hum18-Ser, BAP050-hum19-Ser, orBAP050-hum20-Ser), BAP049-Clone-F, BAP049-Clone-G, BAP049-Clone-H,BAP049-Clone-I, or BAP049-Clone-J, as summarized in Tables 1 and 2, or asequence substantially identical thereto. For example, the nucleic acidmolecule can comprise a nucleotide sequence as set forth in Tables 1 and2, or a sequence substantially identical thereto (e.g., a sequence atleast about 85%, 90%, 95%, 99% or more identical thereto, or whichdiffers by no more than 3, 6, 15, 30, or 45 nucleotides from thesequences shown in Tables 1 and 2).

In another embodiment, the nucleic acid molecule includes one or moreheavy chain framework region and one or more light chain frameworkregion as described herein. The heavy and light chain framework regionsmay be present in the same vector or separate vectors.

In another aspect, the application features host cells and vectorscontaining the nucleic acids described herein. The nucleic acids may bepresent in a single vector or separate vectors present in the same hostcell or separate host cell. The host cell can be a eukaryotic cell,e.g., a mammalian cell, an insect cell, a yeast cell, or a prokaryoticcell, e.g., E. coli. For example, the mammalian cell can be a culturedcell or a cell line. Exemplary mammalian cells include lymphocytic celllines (e.g., NSO), Chinese hamster ovary cells (CHO), human Per C6 cellline (e.g., PER C6 cells from Crucell), COS cells, oocyte cells, andcells from a transgenic animal, e.g., mammary epithelial cell.

In one aspect, the invention features a method of providing an antibodymolecule described herein. The method includes: providing a LAG-3antigen (e.g., an antigen comprising at least a portion of a LAG-3epitope); obtaining an antibody molecule that specifically binds to theLAG-3 polypeptide; and evaluating if the antibody molecule specificallybinds to the LAG-3 polypeptide, or evaluating efficacy of the antibodymolecule in modulating, e.g., inhibiting, the activity of the LAG-3. Themethod can further include administering the antibody molecule to asubject, e.g., a human or non-human animal.

In another aspect, the invention provides, compositions, e.g.,pharmaceutical compositions, which include a pharmaceutically acceptablecarrier, excipient or stabilizer, and at least one of anti-LAG3 antibodymolecule described herein. In one embodiment, the composition, e.g., thepharmaceutical composition, includes a combination of the anti-LAG-3antibody molecule and one or more agents, e.g., a therapeutic agent orother antibody molecule, as described herein. In one embodiment, theantibody molecule is conjugated to a label or a therapeutic agent.

The antibody molecules disclosed herein can inhibit, reduce orneutralize one or more activities of LAG-3. In one embodiment, theanti-LAG-3 antibody molecule results in one or more of: an increase inantigen-dependent stimulation of CD4⁺ T lymphocytes or CD8⁺ Tlymphocytes, an increase in T cell proliferation; an increase inexpression of an activation antigen, e.g., CD25; an increase inexpression of a cytokine, e.g., interferon-gamma (IFN-γ), interleukin-2(IL-2), interleukin-4 (IL-4), chemokine (C—C motif) ligand 3 (CCL3),chemokine (C—C motif) ligand 4 (CCL4), or chemokine (C—C motif) ligand 5(CCL5); a decrease in the suppressor activity of T_(reg) cells, anincrease in T cell homeostasis, an increase in tumor infiltratinglymphocytes, or a decrease in immune evasion by the cancerous cells.Thus, such antibody molecules can be used, alone or in combination, totreat or prevent disorders where enhancing an immune response in asubject is desired.

Uses of the Anti-LAG-3 Antibody Molecules

Accordingly, in another aspect, a method of modulating an immuneresponse in a subject is provided. The method comprises administering tothe subject an antibody molecule disclosed herein (e.g., atherapeutically effective amount of an anti-LAG-3 antibody molecule),alone or in combination with one or more agents or procedures, such thatthe immune response in the subject is modulated. In one embodiment, theantibody molecule restores, enhances, stimulates or increases an immuneresponse in the subject.

The subject can be a mammal, e.g., a primate, preferably a higherprimate, e.g., a human (e.g., a patient having, or at risk of having, adisorder described herein). In one embodiment, the subject is in need ofenhancing an immune response. In some embodiments, the anti-LAG-3antibody molecule restores, enhances or stimulates an antigen-specific Tcell response, e.g., interleukin-2 (IL-2) or interferon-gamma (IFN-γ)production in an antigen-specific T cell response, in the subject. Insome embodiments, the immune response is an anti-tumor response. In oneembodiment, the subject has, or is at risk of, having a disorderdescribed herein, e.g., a cancer or an infectious disorder as describedherein. In certain embodiments, the subject is, or is at risk of being,immunocompromised. For example, the subject is undergoing or hasundergone a chemotherapeutic treatment and/or radiation therapy.Alternatively, or in combination, the subject is, or is at risk ofbeing, immunocompromised as a result of an infection.

In one aspect, a method of treating (e.g., one or more of reducing,inhibiting, or delaying progression) a cancer or tumor in a subject isprovided. The method comprises administering to the subject ananti-LAG-3 antibody molecule described herein, e.g., a therapeuticallyeffective amount of an anti-LAG-3 antibody molecule, alone, e.g., as amonotherapy, or in combination, e.g., with one or more agents orprocedures. In certain embodiments, the anti-LAG-3 antibody molecule isadministered in combination with a modulator of a costimulatory molecule(e.g., an agonist of a costimulatory molecule) or a modulator of aninhibitory molecule (e.g., an inhibitor of an immune checkpointinhibitor), e.g., as described herein. In one embodiment, the anti-LAG-3antibody molecule is administered in combination with an inhibitor oractivator of an immune checkpoint modulator (e.g., a PD-1 inhibitor(e.g., an anti-PD-1 antibody molecule), a PD-L1 inhibitor (e.g., ananti-PD-L1 antibody molecule), a TIM-3 modulator (e.g., a TIM-3activator or inhibitor, e.g., an anti-TIM-3 antibody molecule), or aCTLA-4 inhibitor (e.g., an anti-CTLA4 antibody).

In certain embodiments, the cancer treated with the anti-LAG-3 antibodymolecule, alone or in combination, includes but is not limited to, asolid tumor, a hematological cancer (e.g., leukemia, lymphoma, myeloma),and a metastatic lesion thereof. In one embodiment, the cancer is asolid tumor. Examples of solid tumors include malignancies, e.g.,sarcomas and carcinomas (e.g., adenocarcinomas), of the various organsystems, such as those affecting lung, breast, lymphoid,gastrointestinal or colorectal, genitals and genitourinary tract (e.g.,renal, urothelial, bladder cells), pharynx, CNS (e.g., brain, neural orglial cells), skin (e.g., melanoma), head and neck (e.g., head and necksquamous cell carcinoma (HNCC)), and pancreas. For example, melanoma,colon cancers, gastric cancer, rectal cancer, renal-cell carcinoma,breast cancer (e.g., a breast cancer that does not express one, two orall of estrogen receptor, progesterone receptor, or Her2/neu, e.g., atriple negative breast cancer), liver cancer, a lung cancer (e.g., anon-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/ornon-squamous histology) or small cell lung cancer), prostate cancer,cancer of head or neck (e.g., HPV+ squamous cell carcinoma), cancer ofthe small intestine and cancer of the esophagus. Examples ofhematological cancer include, but is not limited to, leukemia (e.g., amyeloid leukemia, lymphoid leukemia, or chronic lymphocytic leukemia(CLL)), lymphoma (e.g., Hogdkin lymphoma (HL), non-Hogdkin lymphoma(NHL), Diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma, or mantlecell lymphoma (MCL)), and myeloma, e.g., multiple myeloma. The cancermay be at an early, intermediate, late stage or metastatic cancer.

In some embodiments, the cancer is chosen from a colorectal cancer(e.g., CRC), melanoma, e.g., advanced stage melanoma (e.g., stage II-IVmelanoma) or HLA-A2 positive-melanoma; a pancreatic cancer, e.g.,advanced pancreatic cancer; a breast cancer, e.g., metastatic breastcarcinoma or triple negative breast cancer; a head and neck cancer(e.g., HNSCC); an esophageal cancer; a renal cell carcinoma (RCC), e.g.,clear renal cell carcinoma (ccRCC) or metastatic renal cell carcinoma(MRCC); a lung cancer (e.g., NSCLC); a cervical cancer; bladder cancer;or a hematologic malignancy, e.g., a leukemia (e.g., a lymphocyticleukemia), or a lymphoma (e.g., a Hogdkin's lymphoma (HL), anon-Hogdkin's lymphoma (NHL), a diffuse large B-cell lymphoma (DLBCL), amantle cell lymphoma (MCL), or a CLL, e.g., a relapsed or refractorychronic lymphocytic leukemia).

In one embodiment, the cancer is an advanced or unresectable melanomathat does not respond to other therapies. In other embodiments, thecancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation).In yet other embodiments, the anti-LAG-3 antibody molecule is alone(e.g., as a monotherapy), or in combination with one or more secondagents (e.g., a BRAF inhibitor). In one embodiment, the anti-LAG-3antibody molecule is administered in combination with (e.g., before orafter treatment or simultaneously with) an inhibitor of an immunecheckpoint modulator (e.g., a PD-1 inhibitor, a PD-L1 inhibitor, a TIM-3inhibitor, a CEACAM (e.g., CEACAM1 and/or CEACAM5) inhibitor, or a CTLA4inhibitor (e.g., an anti-CLA4 antibody, e.g., ipilimumab)) with orwithout a BRAF inhibitor (e.g., vemurafenib or dabrafenib) to treat amelanoma. In one embodiment, the anti-LAG-3 antibody molecule isadministered in combination with a PD-1 or a PD-L1 inhibitor, e.g., ananti-PD-1 or an anti-PD-L1 antibody molecule, to treat a melanoma asdescribed herein.

In one embodiment, the anti-LAG-3 antibody molecule is administeredalone, e.g., as a monotherapy, or in combination with an inhibitor of animmune checkpoint modulator (e.g., a PD-1 inhibitor (e.g., an anti-PD-1antibody molecule), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibodymolecule), a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), aCEACAM (e.g., CEACAM1 and/or CEACAM5) inhibitor (e.g., an anti-CEACAMantibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody)to treat a head and neck cancer (e.g., HNSCC). In one embodiment, theanti-LAG-3 antibody molecule is administered in combination with a PD-1or a PD-L1 inhibitor, e.g., an anti-PD-1 or anti-PD-L1 antibodymolecule, to treat a head and neck cancer as described herein.

In one embodiment, the anti-LAG-3 antibody molecule is administeredalone, e.g., as a monotherapy, or in combination with an inhibitor oractivator of an immune checkpoint modulator (e.g., a PD-1 inhibitor(e.g., an anti-PD-1 antibody molecule), a PD-L1 inhibitor (e.g., ananti-PD-L1 antibody molecule), a TIM-3 modulator (e.g., a TIM-3activator or inhibitor, e.g., an anti-TIM-3 antibody molecule), a CEACAM(e.g., CEACAM1 and/or CEACAM5) inhibitor (e.g., an anti-CEACAM antibodymolecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody) to treata lung cancer (e.g., a NSCLC). In one embodiment, the anti-LAG-3antibody molecule is administered in combination with a PD-1 or a PD-L1inhibitor, e.g., an anti-PD-1 or anti-PD-L1 antibody molecule, to treata lung cancer (e.g., a NSCLC) as described herein.

In one embodiment, the anti-LAG-3 antibody molecule is administeredalone, e.g., as a monotherapy, or in combination with an inhibitor of animmune checkpoint modulator (e.g., a PD-1 inhibitor (e.g., an anti-PD-1antibody molecule), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibodymolecule), a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), aCEACAM (e.g., CEACAM1 and/or CEACAM5) inhibitor (e.g., an anti-CEACAMantibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody)to treat a gastric cancer. In one embodiment, the anti-LAG-3 antibodymolecule is administered in combination with a PD-1 or a PD-L1inhibitor, e.g., an anti-PD-1 or anti-PD-L1 antibody molecule, to treata gastric cancer as described herein.

In one embodiment, the anti-LAG-3 antibody molecule is administeredalone, e.g., as a monotherapy, or in combination with an inhibitor of animmune checkpoint modulator (e.g., a PD-1 inhibitor (e.g., an anti-PD-1antibody molecule), a PD-L1 inhibitor (e.g., an anti-PD-L1 antibodymolecule), a TIM-3 inhibitor (e.g., an anti-TIM-3 antibody molecule), aCEACAM (e.g., CEACAM1 and/or CEACAM5) inhibitor (e.g., an anti-CEACAMantibody molecule), or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody)to treat a lymphoma (e.g., Hogdkin's lymphoma (HL), non-Hogdkin'slymphoma (NHL), Diffuse large B-cell lymphoma (DLBCL), mantle celllymphoma (MCL), or CLL, e.g., a relapsed or refractory chroniclymphocytic leukemia). In one embodiment, the anti-LAG-3 antibodymolecule is administered in combination with a PD-1 or a PD-L1inhibitor, e.g., an anti-PD-1 or anti-PD-L1 antibody molecule, to treata lymphoma as described herein.

In one embodiment, the cancer microenvironment has an elevated level ofPD-L1 expression. Alternatively, or in combination, the cancermicroenvironment can have increased IFNγ and/or CD8 expression.

In some embodiments, the anti-LAG-3 antibody molecule is administered,alone or in combination with a PD-1 inhibitor (e.g., an anti-PD-1antibody molecule) or a PD-L1 inhibitor (e.g., an anti-PD-L1 antibodymolecule), to treat a subject who has or is identified as having a tumorthat has one or more of high PD-L1 level or expression, or as beingTumor Infiltrating Lymphocyte (TIL)+ (e.g., as having an increasednumber of TILs), or both. In certain embodiments, the subject has, or isidentified as having, a tumor that has high PD-L1 level or expressionand that is TIL+. In some embodiments, the methods described hereinfurther include identifying a subject based on having a tumor that hasone or more of high PD-L1 level or expression or as being TIL+, or both.In certain embodiments, the methods described herein further includeidentifying a subject based on having a tumor that has high PD-L1 levelor expression and as being TIL+. In some embodiments, tumors that areTIL+ are positive for CD8 and IFNγ. In some embodiments, the subjecthas, or is identified as having, a high percentage of cells that arepositive for one, two or more of PD-L1, CD8, and/or IFNγ. In certainembodiments, the subject has or is identified as having a highpercentage of cells that are positive for all of PD-L1, CD8, and IFNγ.

In some embodiments, the methods described herein further includeidentifying a subject based on having a high percentage of cells thatare positive for one, two or more of PD-L1, CD8, and/or IFNγ. In certainembodiments, the methods described herein further include identifying asubject based on having a high percentage of cells that are positive forall of PD-L1, CD8, and IFNγ. In some embodiments, the subject has, or isidentified as having, one, two or more of PD-L1, CD8, and/or IFNγ, andone or more of a lung cancer, e.g., squamous cell lung cancer or lungadenocarcinoma; a head and neck cancer; a squamous cell cervical cancer;a stomach cancer; an esophageal cancer; a thyroid cancer; a melanoma,and/or a nasopharyngeal cancer (NPC). In certain embodiments, themethods described herein further describe identifying a subject based onhaving one, two or more of PD-L1, CD8, and/or IFNγ, and one or more of alung cancer, e.g., squamous cell lung cancer or lung adenocarcinoma; ahead and neck cancer; a squamous cell cervical cancer; a stomach cancer;a thyroid cancer; a melanoma, and or a nasopharyngeal cancer.

Methods and compositions disclosed herein are useful for treatingmetastatic lesions associated with the aforementioned cancers.

In a further aspect, the invention provides a method of treating aninfectious disease in a subject, comprising administering to a subject atherapeutically effective amount of an anti-LAG-3 antibody moleculedescribed herein, alone or in combination with one or more agents orprocedures. The antibodies of the invention are preferred for use in themethod although other anti-LAG-3 antibodies, or antigen-bindingfragments thereof, can be used instead (or in combination with ananti-LAG-3 antibody molecule described herein).

In one embodiment, the infectious disease is hepatitis (e.g., hepatitisB infection). In certain embodiment, the anti-LAG-3 antibody molecule isadministered in combination with a hepatitis B antigen or vaccine, andoptionally in combination with an aluminum-containing adjuvant.

In another embodiment, the infectious disease is influenza. In certainembodiment, the anti-LAG-3 antibody molecule is administered incombination with an influenza antigen or vaccine.

Still further, the invention provides a method of enhancing an immuneresponse to an antigen in a subject, comprising administering to thesubject: (i) the antigen; and (ii) an anti-LAG-3 antibody molecule, suchthat an immune response to the antigen in the subject is enhanced. Theantigen can be, for example, a tumor antigen, a viral antigen, abacterial antigen or an antigen from a pathogen.

The anti-LAG-3 antibody molecule, alone or in combination, can beadministered to the subject systemically (e.g., orally, parenterally,subcutaneously, intravenously, rectally, intramuscularly,intraperitoneally, intranasally, transdermally, or by inhalation orintracavitary installation), topically, or by application to mucousmembranes, such as the nose, throat and bronchial tubes.

Dosages and therapeutic regimens of the anti-LAG-3 antibody molecule canbe determined by a skilled artisan. In certain embodiments, theanti-LAG-3 antibody molecule is administered by injection (e.g.,subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g.,about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 10 mg/kg, or about1 mg/kg, 3 mg/kg, or 10 mg/kg. The dosing schedule can vary from e.g.,once a week to once every 2, 3, or 4 weeks. In one embodiment, theanti-LAG-3 antibody molecule is administered at a dose from about 10 to20 mg/kg every other week. In one embodiment, the anti-LAG-3 antibodymolecule is administered (e.g., intravenously) at a dose from about 3 to800 mg, e.g., about 3, 20, 80, 240, or 800 mg. In certain embodiments,the anti-LAG-3 antibody molecule is administered alone at a dose fromabout 20 to 800 mg, e.g., about 3, 20, 80, 240, or 800 mg. In otherembodiments, the anti-LAG-3 antibody molecule is administered at a dosefrom about 3 to 240 mg, e.g., about 3, 20, 80, or 240 mg, when it iscombined with a second agent or therapeutic modality, e.g., a secondagent or therapeutic modality described herein. In one embodiment, theanti-LAG-3 antibody molecule is administered every 2 weeks (e.g., duringweeks 1, 3, 5, 7) during each 8 week cycle, e.g., up to 96 weeks.

The antibody molecules described herein are preferred for use in themethods described herein, although other anti-LAG-3 antibodies can beused instead, or in combination with an anti-LAG-3 antibody molecule ofthe invention.

Combination Therapies

The methods and compositions described herein can be used in combinationwith other agents or therapeutic modalities. In one embodiment, themethods described herein include administering to the subject ananti-LAG-3 antibody molecule as described herein, in combination with anagent or therapeutic procedure or modality, in an amount effective totreat or prevent a disorder. The anti-LAG-3 antibody molecule and theagent or therapeutic procedure or modality can be administeredsimultaneously or sequentially in any order. Any combination andsequence of the anti-LAG-3 antibody molecules and other therapeuticagents, procedures or modalities (e.g., as described herein) can beused. The antibody molecule and/or other therapeutic agents, proceduresor modalities can be administered during periods of active disorder, orduring a period of remission or less active disease. The antibodymolecule can be administered before the other treatment, concurrentlywith the treatment, post-treatment, or during remission of the disorder.

In certain embodiments, the methods and compositions described hereinare administered in combination with one or more of other antibodymolecules, chemotherapy, other anti-cancer therapy (e.g., targetedanti-cancer therapies, gene therapy, viral therapy, RNA therapy bonemarrow transplantation, nanotherapy, or oncolytic drugs), cytotoxicagents, immune-based therapies (e.g., cytokines or cell-based immunetherapies), surgical procedures (e.g., lumpectomy or mastectomy) and/orradiation procedures, or a combination of any of the foregoing. Theadditional therapy may be in the form of adjuvant or neoadjuvanttherapy. In some embodiments, the additional therapy is an enzymaticinhibitor (e.g., small molecule enzymatic inhibitor) or a metastaticinhibitor.

Exemplary cytotoxic agents that can be administered in combination withinclude antimicrotubule agents, topoisomerase inhibitors,anti-metabolites, mitotic inhibitors, alkylating agents, anthracyclines,vinca alkaloids, intercalating agents, agents capable of interferingwith a signal transduction pathway, agents that promote apoptosis,proteosome inhibitors, and radiation (e.g., local or whole bodyirradiation (e.g., gamma irradiation). In other embodiments, theadditional therapy is surgery or radiation, or a combination thereof. Inother embodiments, the additional therapy is a therapy targeting one ormore of PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or a tubulininhibitor. Exemplary other antibody molecules that can be administeredin combination include, but are not limited to, checkpoint inhibitors(e.g., anti-PD-1, anti-PD-L1); antibodies that stimulate an immune cell(e.g., agonistic GITR or CD137 antibodies); anti-cancer antibodies(e.g., rituximab (Rituxan® or MabThera®), trastuzumab (Herceptin®),cetuximab (Erbitux®), among others.

Alternatively, or in combination with the aforesaid combinations, themethods and compositions described herein can be administered incombination with one or more of: an immunomodulator (e.g., an activatorof a costimulatory molecule or an inhibitor of an immunoinhibitorymolecule, e.g., an immune checkpoint molecule); a vaccine, e.g., atherapeutic cancer vaccine; or other forms of cellular immunotherapy.

Exemplary non-limiting combinations and uses of the anti-LAG-3 antibodymolecules include the following.

In certain embodiments, the anti-LAG-3 antibody molecule is administeredin combination with a modulator of a costimulatory molecule (e.g., anagonist of a costimulatory molecule) or a modulator of an inhibitorymolecule (e.g., an inhibitor of an immune checkpoint inhibitor).

In one embodiment, the anti-LAG-3 antibody molecule is administered incombination with a modulator, e.g., an agonist, of a costimulatorymolecule. In one embodiment, the agonist of the costimulatory moleculeis chosen from an agonist (e.g., an agonistic antibody or solublefusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS(CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT,NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.

In one embodiment, the anti-LAG-3 antibody molecule is administered incombination with an inhibitor of an inhibitory (or immune checkpoint)molecule chosen from PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, VISTA, BTLA,TIGIT, LAIR1, CD160, 2B4, CEACAM (e.g., CEACAM-1 and/or CEACAM-5),and/or TGFR beta. Inhibition of an inhibitory molecule can be performedby inhibition at the DNA, RNA or protein level. In embodiments, aninhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used toinhibit expression of an inhibitory molecule. In other embodiments, theinhibitor of an inhibitory signal is, a polypeptide e.g., a solubleligand, or an antibody or antibody fragment, that binds to theinhibitory molecule. In one embodiment, the inhibitor is a solubleligand (e.g., a CTLA-4-Ig), or an antibody or antibody fragment thatbinds to PD-1, PD-L1, PD-L2 or CTLA-4.

For example, the anti-LAG-3 antibody molecule can be administered incombination with an inhibitor of, e.g., an antibody or antibody fragmentthat binds to, PD-1, PD-L, PD-L2 or CTLA-4, to treat a cancer (e.g., acancer chosen from: a colorectal cancer (e.g., CRC); a melanoma, e.g.,advanced stage melanoma (e.g., stage II-IV melanoma) or HLA-A2positive-melanoma; a pancreatic cancer, e.g., advanced pancreaticcancer; a breast cancer, e.g., metastatic breast carcinoma or triplenegative breast cancer; a head and neck cancer (e.g., HNSCC); anesophageal cancer; a renal cell carcinoma (RCC), e.g., clear renal cellcarcinoma (ccRCC) or metastatic renal cell carcinoma (MRCC); a lungcancer (e.g., NSCLC); a cervical cancer; a bladder cancer; or ahematologic malignancy, e.g., a leukemia (e.g., a lymphocytic leukemia),or a lymphoma (e.g., a Hogdkin's lymphoma (HL), a non-Hogdkin's lymphoma(NHL), a diffuse large B-cell lymphoma (DLBCL), a mantle cell lymphoma(MCL), or a CLL, e.g., a relapsed or refractory chronic lymphocyticleukemia).

In one embodiment, the anti-LAG-3-1 antibody molecule is administered incombination with (e.g., before, with, or after) treatment with ananti-CTLA4 antibody (e.g., ipilimumab) with or without a BRAF inhibitor(e.g., vemurafenib or dabrafenib).

In another embodiment, the anti-LAG-3 antibody molecule is administeredin combination with an anti-PD-1 antibody (e.g., Nivolumab orPembrokizumab) or antigen-binding fragment thereof. In anotherembodiment, the anti-LAG-3 antibody molecule is administered incombination with an anti-TIM-3 antibody or antigen-binding fragmentthereof. In still another embodiment, the anti-LAG-3 antibody moleculeis administered in combination with an anti-PD-L1 antibody orantigen-binding fragment thereof. In yet other embodiments, theanti-LAG-3 antibody molecule is administered in combination with ananti-PD-1 antibody and an anti-TIM-3 antibody (or antigen-bindingfragments thereof). In certain embodiments, the anti-LAG-3 antibodymolecule is administered in combination with an anti-PD-1 antibody andan anti-PD-L1 antibody (or antigen-binding fragments thereof). Incertain embodiments, the anti-LAG-3 antibody molecule is administered incombination with an anti-TIM-3 antibody and an anti-PD-L1 antibody (orantigen-binding fragments thereof).

In another embodiment, the anti-LAG-3 antibody molecule is administeredin combination with a CEACAM inhibitor (e.g., CEACAM-1 and/or CEACAM-5inhibitor), e.g., an anti-CEACAM antibody molecule. In anotherembodiment, the anti-LAG-3 antibody molecule is administered incombination with a CEACAM-1 inhibitor, e.g., an anti-CEACAM-1 antibodymolecule. In another embodiment, the anti-LAG-3 antibody molecule isadministered in combination with a CEACAM-5 inhibitor, e.g., ananti-CEACAM-5 antibody molecule.

In yet other embodiments, the anti-LAG-3 antibody molecule isadministered in combination with an anti-CEACAM (e.g., anti-CEACAM-1and/or anti-CEACAM-5) antibody molecule and an anti-PD-1 antibodymolecule. In yet other embodiments, the anti-LAG-3 antibody molecule isadministered in combination with an anti-CEACAM (e.g., anti-CEACAM-1and/or anti-CEACAM-5) antibody molecule and an anti-TIM-3 antibodymolecule. In yet other embodiments, the anti-LAG-3 antibody molecule isadministered in combination with an anti-CEACAM (e.g., anti-CEACAM-1and/or anti-CEACAM-5) antibody molecule and an anti-PD-L1 antibodymolecule. The combination of antibodies recited herein can beadministered separately, e.g., as separate antibodies or antigen-bindingfragments thereof, or linked, e.g., as a bispecific or trispecificantibody molecule. In one embodiment, a bispecific antibody thatincludes an anti-LAG-3 antibody molecule and one of: an anti-TIM-3antibody, anti-CEACAM (e.g., anti-CEACAM-1 and/or anti-CEACAM-5)antibody, anti-PD-L1 antibody, or anti-PD-1 antibody, or anantigen-binding fragment thereof, is administered. In certainembodiments, the combination of antibodies recited herein is used totreat a cancer, e.g., a cancer as described herein (e.g., a solid tumoror a hematological malignancy). In one embodiment, the anti-LAG-3antibody molecule is administered in combination with an anti-PD-1 oranti-PD-L1 antibody to treat a solid tumor.

In other embodiments, the anti-LAG-3 antibody molecule is administeredin combination with a cytokine. The cytokine can be administered as afusion molecule to the anti-LAG-3 antibody molecule, or as separatecompositions. In one embodiment, the anti-LAG-3 antibody is administeredin combination with one, two, three or more cytokines, e.g., as a fusionmolecule or as separate compositions. In one embodiment, the cytokine isan interleukin (IL) chosen from one, two, three or more of IL-1, IL-2,IL-12, IL-12, IL-15 or IL-21. In one embodiment, a bispecific antibodymolecule has a first binding specificity to a first target (e.g., toLAG-3), a second binding specificity to a second target (e.g., PD-1,TIM-3, or PD-L1), and is optionally linked to an interleukin (e.g.,IL-12) domain e.g., full length IL-12 or a portion thereof. In certainembodiments, the combination of anti-LAG-3 antibody molecule and thecytokine described herein is used to treat a cancer, e.g., a cancer asdescribed herein (e.g., a solid tumor).

In other embodiments, the anti-LAG-3 antibody molecule is administeredin combination with a vaccine, e.g., a therapeutic cancer vaccine, orother forms of cellular immunotherapy. In one embodiment, the vaccine ispeptide-based, DNA-based, RNA-based, or antigen-based, or a combinationthereof. In embodiments, the vaccine comprises one or more peptides,nucleic acids (e.g., DNA or RNA), antigens, or a combination thereof. Incertain embodiments, the cancer vaccine comprises an adjuvant (e.g.,aluminium phosphate or aluminum hydroxide). In some embodiments, themethods described herein are administered in combination with one ormore of surgical removal of a tissue, chemotherapy, or other anti-cancertherapy and the primary or sole target will be metastatic lesions, e.g.,metastases in the bone marrow or lymph nodes.

In one embodiment, the cancer is a melanoma, e.g., an advanced stagemelanoma (e.g., stage II-IV melanoma) or HLA-A2 positive melanoma. Incertain embodiment, the anti-LAG-3 antibody molecule is administered incombination with a tumor antigenic peptide, e.g., one or more HLA-A2peptides, and optionally in combination with an adjuvant, e.g.,Montanide™. Exemplary tumor peptides that can be administered incombination with the anti-LAG-3 antibody molecule include one or more ofTyrosinase.A2, MAGE-C2.A2, NY-ESO-1b.A2, MAGE-4.A2, MAGE-3.A2,MAGE-1.A2, NA17.A2 (GnTV), and MAGE-10.A2.

In another embodiment, the cancer is a pancreatic cancer, e.g., advancedpancreatic cancer. In certain embodiment, the antibody molecule can beadministered in combination with a chemotherapeutic agent, e.g.,gemcitabine.

In another embodiment, the cancer is a breast cancer, e.g., metastaticbreast carcinoma or triple negative breast cancer. In certainembodiment, the antibody molecule can be administered in combinationwith a chemotherapeutic agent, e.g., paclitaxel.

In another embodiment, the cancer is a renal cell carcinoma, e.g., clearcell carcinoma, advanced (e.g., stage IV) or metastatic renal cellcarcinoma (MRCC).

In another embodiment, the cancer is a cancer of head or neck, e.g.,HPV+ squamous cell carcinoma.

In another embodiment, the anti-LAG-3 antibody molecule is administeredin combination with an antigen. For example, the anti-LAG-3 antibodymolecule can be combined with a hepatitis B antigen (e.g., Engerix B).In other embodiments, the anti-LAG-3 antibody molecule is administeredin combination with a flu antigen.

The anti-LAG-3 antibody molecule can be used alone in unconjugated form,or can be bound to a substance, e.g., a cytotoxic agent or moiety (e.g.,a therapeutic drug; a compound emitting radiation; molecules of plant,fungal, or bacterial origin; or a biological protein (e.g., a proteintoxin) or particle (e.g., a recombinant viral particle, e.g., via aviral coat protein). For example, the antibody can be coupled to aradioactive isotope such as an α-, β-, or γ-emitter, or a β- andγ-emitter.

Additional Combination Therapies

The methods and compositions described herein (e.g., LAG-3 antibodiesand methods of using them) can be used in combination with other agentsor therapeutic modalities, e.g., a second therapeutic agent chosen fromone or more of the agents listed in Table 7. In one embodiment, themethods described herein include administering to the subject ananti-LAG-3 antibody molecule as described herein (optionally incombination with one or more inhibitors of PD-1, PD-L1, TIM-3, CEACAM(e.g., CEACAM-1 and/or CEACAM-5), or CTLA-4)), further includeadministration of a second therapeutic agent chosen from one or more ofthe agents listed in Table 7, in an amount effective to treat or preventa disorder, e.g., a disorder as described herein, e.g., a cancer. Whenadministered in combination, the anti-LAG-3 antibody molecule, theadditional agent (e.g., second or third agent), or all, can beadministered in an amount or dose that is higher, lower or the same thanthe amount or dosage of each agent used individually, e.g., as amonotherapy. In certain embodiments, the administered amount or dosageof the anti-LAG-3 antibody, the additional agent (e.g., second or thirdagent), or all, is lower (e.g., at least 20%, at least 30%, at least40%, or at least 50%) than the amount or dosage of each agent usedindividually, e.g., as a monotherapy. In other embodiments, the amountor dosage of the anti-LAG-3 antibody, the additional agent (e.g., secondor third agent), or all, that results in a desired effect (e.g.,treatment of cancer) is lower (e.g., at least 20%, at least 30%, atleast 40%, or at least 50% lower).

In other embodiments, the second therapeutic agent is chosen from one ormore of the agents listed in Table 7. In one embodiment, the cancer ischosen from a lung cancer (e.g., a non-small cell lung cancer (NSCLC)(e.g., a NSCLC with squamous and/or non-squamous histology, or a NSCLCadenocarcinoma), or disclosed in a publication listed in Table 7. Insome embodiments, the second therapeutic agent is chosen from one ormore of: 1) a protein kinase C (PKC) inhibitor; 2) a heat shock protein90 (HSP90) inhibitor; 3) an inhibitor of a phosphoinositide 3-kinase(PI3K) and/or target of rapamycin (mTOR); 4) an inhibitor of cytochromeP450 (e.g., a CYP17 inhibitor or a 17alpha-Hydroxylase/C17-20 Lyaseinhibitor); 5) an iron chelating agent; 6) an aromatase inhibitor; 7) aninhibitor of p53, e.g., an inhibitor of a p53/Mdm2 interaction; 8) anapoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosteronesynthase inhibitor; 11) a smoothened (SMO) receptor inhibitor; 12) aprolactin receptor (PRLR) inhibitor; 13) a Wnt signaling inhibitor; 14)a CDK4/6 inhibitor; 15) a fibroblast growth factor receptor 2(FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) aninhibitor of macrophage colony-stimulating factor (M-CSF); 17) aninhibitor of one or more of c-KIT, histamine release, Flt3 (e.g.,FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (e.g.,FLK-1/KDR), PDGFRbeta, c-KIT or Raf kinase C; 19) a somatostatin agonistand/or a growth hormone release inhibitor; 20) an anaplastic lymphomakinase (ALK) inhibitor; 21) an insulin-like growth factor 1 receptor(IGF-1R) inhibitor; 22) a P-Glycoprotein 1 inhibitor; 23) a vascularendothelial growth factor receptor (VEGFR) inhibitor; 24) a BCR-ABLkinase inhibitor; 25) an FGFR inhibitor; 26) an inhibitor of CYP11B2;27) a HDM2 inhibitor, e.g., an inhibitor of the HDM2-p53 interaction;28) an inhibitor of a tyrosine kinase; 29) an inhibitor of c-MET; 30) aninhibitor of JAK; 31) an inhibitor of DAC; 32) an inhibitor of11β-hydroxylase; 33) an inhibitor of IAP; 34) an inhibitor of PIMkinase; 35) an inhibitor of Porcupine; 36) an inhibitor of BRAF, e.g.,BRAF V600E or wild-type BRAF; 37) an inhibitor of HER3; 38) an inhibitorof MEK; or 39) an inhibitor of a lipid kinase, e.g., as described hereinand in Table 7.

In one embodiment, the second therapeutic agent is chosen from one ormore of: Compound A8, Compound A17, Compound A23, Compound A24, CompoundA27, Compound A29, Compound A33, and Compound A13.

In other embodiments, the second therapeutic agent is chosen from one ormore of: Compound A5, Compound A8, Compound A17, Compound A23, CompoundA24, Compound A29, and Compound A40.

In other embodiments, the second therapeutic agent is chosen from one ormore of: Compound A9, Compound A16, Compound A17, Compound A21, CompoundA22, Compound A25, Compound A28, Compound A48, and Compound 49.

In embodiments, the second therapeutic agent is administered at atherapeutic or lower-than therapeutic dose. In certain embodiments, theconcentration of the second therapeutic agent that is required toachieve inhibition, e.g., growth inhibition, is lower when the secondtherapeutic agent is administered in combination with the anti-LAG-3antibody molecule than when the second therapeutic agent is administeredindividually. In certain embodiments, the concentration of theanti-LAG-3 antibody molecule that is required to achieve inhibition,e.g., growth inhibition, is lower when the anti-LAG-3 antibody moleculeis administered in combination with the second therapeutic agent thanwhen the anti-LAG-3 antibody molecule is administered individually. Incertain embodiments, in a combination therapy, the concentration of thesecond therapeutic agent that is required to achieve inhibition, e.g.,growth inhibition, is lower than the therapeutic dose of the secondtherapeutic agent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%,40-50%, 50-60%, 60-70%, 70-80%, or 80-90% lower. In certain embodiments,in a combination therapy, the concentration of the anti-LAG-3 antibodymolecule that is required to achieve inhibition, e.g., growthinhibition, is lower than the therapeutic dose of the anti-PD-1 antibodymolecule as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%,60-70%, 70-80%, or 80-90% lower.

Detection

In another aspect, the invention features methods for detecting thepresence of LAG-3 in a sample, e.g., in vitro or in vivo (e.g., abiological sample, e.g., serum, semen or urine, or a tissue biopsy,e.g., from a hyperproliferative or cancerous lesion). The subject methodcan be used to evaluate (e.g., monitor treatment or progression of,diagnose and/or stage a disorder described herein, e.g., ahyperproliferative or cancerous disorder, in a subject). The methodincludes: (i) contacting the sample with (and optionally, a reference,e.g., a control sample), or administering to the subject, an anti-LAG-3antibody molecule as described herein, under conditions that allowinteraction to occur, and (ii) detecting formation of a complex betweenthe antibody molecule, and the sample (and optionally, the reference,e.g., control, sample). Formation of the complex is indicative of thepresence of LAG-3, and can indicate the suitability or need for atreatment described herein. The method can involve animmunohistochemistry, immunocytochemistry, flow cytometry (e.g., FACS),antibody molecule complexed magnetic beads, ELISA assays, PCR-techniques(e.g., RT-PCR).

Typically, the anti-LAG-3 antibody molecule used in the in vivo and invitro diagnostic methods is directly or indirectly labeled with adetectable substance to facilitate detection of the bound or unboundbinding agent. Suitable detectable substances include variousbiologically active enzymes, prosthetic groups, fluorescent materials,luminescent materials, paramagnetic (e.g., nuclear magnetic resonanceactive) materials, and radioactive materials.

Additional embodiments provide a method of treating a cancer,comprising: identifying in a sample (e.g., a subject's sample comprisingcancer cells and optionally immune cells such as TILs) the presence ofone, two or all of PD-L1, CD8, or IFN-γ, thereby providing a value forone, two or all of PD-L1, CD8, and IFN-γ. The method can further includecomparing the PD-L1, CD8, and/or IFN-γ values to a reference value,e.g., a control value. If the PD-L, CD8, and/or IFN-γ values are greaterthan the reference value, e.g., the control values, administering atherapeutically effective amount of an anti-LAG-3 antibody (e.g., ananti-LAG-3 antibody described herein), alone or incombination with ananti-PD-1 antibody molecule, an anti-PD-L1 antibody molecule, or both,to the subject, optionally in combination with one or more other agents,thereby treating the cancer. The cancer may be, e.g., a cancer describedherein, such as lung cancer (squamous), lung cancer (adenocarcinoma),head and neck cancer, cervical cancer (squamous), stomach cancer,thyroid cancer, melanoma, nasopharyngeal cancer, or breast cancer, e.g.,TN breast cancer, e.g., IM-TN breast cancer. In some embodiments, thecancer is ER+ breast cancer or pancreatic cancer.

Also provided is a method of treating a cancer, comprising: testing asample (e.g., a subject's sample comprising cancer cells) for thepresence of PD-L1, thereby identifying a PD-L1 value, comparing thePD-L1 value to a control value, and if the PD-L1 value is greater thanthe control value, administering a therapeutically effective amount ofan anti-LAG-3 antibody (e.g., an anti-LAG-3 antibody described herein),alone or incombination with an anti-PD-1 antibody molecule, ananti-PD-L1 antibody molecule, or both, to the subject, optionally incombination with one or more other agents, thereby treating the cancer.The cancer may be, e.g., a cancer as described herein, such as cancer isnon-small cell lung (NSCLC) adenocarcinoma (ACA), NSCLC squamous cellcarcinoma (SCC), or hepatocellular carcinoma (HCC).

In another aspect, the invention features diagnostic or therapeutic kitsthat include the anti-LAG-3 antibody molecules described herein andinstructions for use.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

Other features, objects, and advantages of the invention will beapparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the amino acid sequences of the light (SEQ ID NO: 16) andheavy (SEQ ID NO: 6) chain variable regions of murine anti-LAG-3 mAbBAP050. The light and heavy chain CDR sequences based on Kabat numberingare underlined. The light and heavy chain CDR sequences based on Chothianumbering are shown in bold italics.

FIG. 2 depicts the amino acid sequences of the light (SEQ ID NO: 16) andheavy (SEQ ID NO: 6) chain variable regions of murine anti-LAG-3 mAbBAP050 aligned with the germline sequences (SEQ ID NOs: 290-291,respectively, in order of appearance). The upper and lower sequences arethe germline (GL) and BAP050 (Mu mAb) sequences, respectively. The lightand heavy chain CDR sequences based on Kabat numbering are underlined.The light and heavy chain CDR sequences based on Chothia numbering areshown in bold italics. “-” means identical amino acid residue.

FIG. 3 depicts bar graphs showing the results of FACS binding analysisfor the twenty humanized BAP050 clones (BAP050-hum01 to BAP050-hum20)and the chimeric mAb (BAP050-chi). The antibody concentrations are 200,100, 50, 25 and 12.5 ng/ml from the leftmost bar to the rightmost barfor each tested mAb.

FIG. 4 depicts the structural analysis of the humanized BAP049 clones(a, b, c, d, e, f, g represent various types of framework regionsequences). The concentrations of the mAbs in the samples are alsoshown.

FIG. 5A-5B depicts the binding affinity and specificity of humanizedmAbs measured in a competition binding assay using a constantconcentration of FITC-labeled murine mAb, serial dilutions of the testantibodies, and LAG-3-expressing CHO cells. Experiment was performedtwice, and the results are shown in FIGS. 5A and 5B, respectively.

FIG. 6 depicts the ranking of humanized BAP050 clones based on FACSdata, competition binding and structural analysis. The concentrations ofthe mAbs in the samples are also shown.

FIG. 7 depicts the binding affinity and specificity of huBAP050(Ser)clones measured in a competition binding assay using a constantconcentration of FITC-labeled murine mAb, serial dilutions of the testantibodies, and LAG-3-expressing CHO cells. HuBAP050(Ser) clones, suchas, BAP050-hum01-Ser, BAP050-hum02-Ser, BAP050-hum05-Ser,BAP050-hum09-Ser, BAP050-hum11-Ser, BAP050-hum12-Ser, andBAP050-hum13-Ser, were evaluated. Murine mAb BAP050, chimeric mAbBAP050-chi, and humanized BAP050-hum01, BAP050-hum02, BAP050-hum05,BAP050-hum09, BAP050-hum11, BAP050-hum12, and BAP050-hum13 were alsoincluded in the analyses.

FIG. 8 depicts blocking of binding of LAG-3-Ig to Daudi cells byhuBAP050(Ser) clones. HuBAP050(Ser) clones, such as, BAP050-hum01-Ser,BAP050-hum02-Ser, BAP050-hum05-Ser, BAP050-hum09-Ser, BAP050-hum11-Ser,BAP050-hum12-Ser, and BAP050-hum13-Ser, were evaluated. Murine mAbBAP050 and chimeric mAb BAP050-chi were also included in the analyses.

FIGS. 9A-9B depict the alignment of heavy chain variable domainsequences for the twenty humanized BAP050 clones and BAP050 chimera(BAP050-chi). In FIG. 9A, all of the sequences are shown (SEQ ID NOs:20, 28, 28, 28, 28, 28, 28, 28, 28, 28, 28, 64, 64, 64, 64, 64, 68, 72,72, 76 and 80, respectively, in order of appearance). In FIG. 9B, onlyamino acid sequences that are different from mouse sequence are shown(SEQ ID NOs: 20, 28, 28, 28, 28, 28, 28, 28, 28, 28, 28, 64, 64, 64, 64,64, 68, 72, 72, 76 and 80, respectively, in order of appearance).

FIGS. 10A-10B depict the alignment of light chain variable domainsequences for the twenty humanized BAP050 clones and BAP050 chimera(BAP050-chi). In FIG. 10A, all of the sequences are shown (SEQ ID NOs:24, 32, 36, 36, 36, 292, 292, 292, 44, 48, 52, 56, 56, 60, 60, 60, 60,84, 88, 92 and 96, respectively, in order of appearance). In FIG. 10B,only amino acid sequences that are different from mouse sequence areshown (SEQ ID NOs: 24, 32, 36, 36, 36, 292, 292, 292, 44, 48, 52, 56,56, 60, 60, 60, 60, 84, 88, 92 and 96, respectively, in order ofappearance).

FIG. 11 shows exemplary cancers having relatively high proportions ofpatients that are triple-positive for PD-L1/CD8/IFN-γ.

FIG. 12 shows exemplary ER+ breast cancer and pancreatic cancer havingrelatively low proportions for patients that are triple positive forPD-L1/CD8/IFN-γ.

FIG. 13 shows the proportion of exemplary breast cancer patients thatare triple positive for PD-L1/CD8/IFN-γ.

FIG. 14 shows the proportion of exemplary colon cancer patients that aretriple positive for PD-L1/CD8/IFN-γ.

BRIEF DESCRIPTION OF THE TABLES

Table 1 is a summary of the amino acid and nucleotide sequences for themurine, chimeric and humanized anti-LAG-3 antibody molecules. Theantibody molecules include murine mAb BAP050 and chimeric mAbsBAP050-chi, humanized mAbs BAP050-hum01 to BAP050-hum20,BAP050-hum01-Ser to BAP050-hum15-Ser, BAP050-hum18-Ser toBAP050-hum20-Ser, and BAP050-Clone-F to BAP050-Clone-J. The amino acidand nucleotide sequences of the heavy and light chain CDRs, the aminoacid and nucleotide sequences of the heavy and light chain variableregions, and the amino acid and nucleotide sequences of the heavy andlight chains are shown in this Table.

Table 2 depicts the amino acid and nucleotide sequences of the heavy andlight chain framework regions for humanized mAbs BAP050-hum01 toBAP049-hum20, BAP050-hum01-Ser to BAP050-hum15-Ser, BAP050-hum18-Ser toBAP050-hum20-Ser, and BAP049-Clone-F to BAP049-Clone-J.

Table 3 depicts the constant region amino acid sequences of human IgGheavy chains and human kappa light chain.

Table 4 shows the amino acid sequences of the heavy and light chainleader sequences for humanized mAbs BAP050-Clone-F to BAP050-Clone-J.

Table 5 is a summary of yield, titre, monomer content and endotoxinlevels for exemplary humanized BAP050 mAbs expressed in CHO cells.

Table 6 shows the charge isoforms as detected by Novex IEF analysis forexemplary humanized BAP050 mAbs expressed in CHO cells.

Table 7 is a summary of selected therapeutic agents that can beadministered in combination with the anti-LAG-3 antibody molecules andother immunomodulators (e.g., one or more of: an activator of acostimulatory molecule and/or an inhibitor of an immune checkpointmolecule) described herein. Table 7 provides from left to right thefollowing: the Compound Designation of the second therapeutic agent, theCompound structure, and patent publication(s) disclosing the Compound.

DETAILED DESCRIPTION

The immune system has the capability of recognizing and eliminatingtumor cells; however, tumors can use multiple strategies to evadeimmunity. Blockade of immune checkpoints is one of the approaches toactivating or reactivating therapeutic antitumor immunity. LymphocyteActivation Gene-3 (LAG-3) has been described as an inhibitory receptorin the immunological synapse (Chen and Flies (2013) Nat Rev Immunol.13(4):227-42). Thus, blocking of LAG-3 can lead to enhancement ofantitumor immunity.

Several cell types express LAG-3. For example, LAG-3 is expressed onactivated CD4⁺ and CD8⁺ T cells, T_(reg) cells, natural killer (NK)cells, and plasmacytoid dendritic cells (DCs). LAG-3 is expressed intumor-infiltrating lymphocytes, e.g., infiltrating lymphocytes in headand neck squamous cell carcinoma (HNSCC). LAG-3 is expressed on highlysuppressive induced and natural Tregs. For example, highly suppressiveFoxP3+ nTregs and FoxP3− iTregs are LAG-3 positive in melanoma andcolorectal cancer (Camisaschi et al. (2010) J. Immunol.184(11):6545-6551; Scurr et al. (2014) Mucosal. Immunol. 7(2):428-439).

LAG-3 negatively regulates T cell signaling and functions. Ligands forLAG-3 includes, e.g., MHC Class II and L-SECtin. Anti-LSECtin has beenshown to inhibit B16 melanoma cell growth (Xu et al. (2014) Cancer Res.74(13):3418-3428). Blockade of LAG-3 can restore activities of effectorcells, dimish suppressor activity of T_(regs), and/or enhance anti-PD-1antitumor activity.

LAG-3 is typically though not exclusively co-expressed on PD-1⁺ cellsand single blockade can restore in vitro activities of the cells. Thedegree of CD8⁺ T cell exhaustion, e.g., as shown by the percentages ofdual IFN-γ/TNF-α producers, correlates with the number of inhibitoryreceptors expressed (Blackburn et al. (2009) Nat. Immunol. 10(1):29-37). High PD-1/LAG-3 expression correlates with T cell infiltrationin melanoma. Co-blockade of LAG-3 with anti-PD-1 or PD-L1 can result intumor suppressive activities in preclinical models. For example,anti-LAG-3 and anti-PD-1 blockade show efficacy in SalN fibrosarcoma andMC38 colon carcinoma models (Woo et al. (2012) Cancer Res.72(4):917-27).

LAG-3 blockade is also efficacious in a lymphocytic choriomeningitisvirus (LCMV) model. For example, PD-L1 plus LAG-3 blockade duringchronic LCMV infection enhances antiviral CD8+ T cell responses(Blackburn et al. (2009) Nat. Immunol. 10(1): 29-37).

Accordingly, the present invention provides, at least in part, antibodymolecules (e.g., humanized antibody molecules) that bind to LymphocyteActivation Gene-3 (LAG-3) with high affinity and specificity. In oneembodiment, humanized antibodies against LAG-3 are disclosed, which showlow immunogenicity. For example, humanized BAP050 antibodies were foundto have a risk score of less than 1200, 1150, 1100, 1050, 1000, 950,900, 850, or 800, according to the T cell epitope assays describedherein. In other embodiments, selected combination of framework regions,e.g., as shown in FIGS. 4 and 6, were shown to have distinct productionefficiencies and binding properties.

Additional aspects of the invention include nucleic acid moleculesencoding the antibody molecules, expression vectors, host cells andmethods for making the antibody molecules. Immunoconjugates, multi- orbispecific molecules and pharmaceutical compositions comprising theantibody molecules are also provided. The anti-LAG-3 antibody moleculesdisclosed herein can be used to treat, prevent and/or diagnose cancerousor malignant disorders (e.g., cancers such melanoma, e.g., advancedstage melanoma; pancreatic cancer, e.g., advanced pancreatic cancer;solid tumors; breast cancer, e.g., metastatic breast carcinoma; renalcell carcinoma, e.g., advanced or metastatic renal cell carcinoma (MRCC)or clear cell renal cell carcinoma), as well as infectious diseases(e.g., hepatitis, e.g., hepatitis B; influenza). Thus, methods fordetecting LAG-3, as well as methods for treating various disorders,including cancer and infectious diseases using the anti-LAG-3 antibodymolecules, alone or in combination, are disclosed herein.

The term “Lymphocyte Activation Gene-3” or “LAG-3” include all isoforms,mammalian, e.g., human LAG-3, species homologs of human LAG-3, andanalogs comprising at least one common epitope with LAG-3. The aminoacid and nucleotide sequences of LAG-3, e.g., human LAG-3, is known inthe art, e.g., Triebel et al. (1990) J. Exp. Med. 171:1393-1405.

Additional terms are defined below and throughout the application.

As used herein, the articles “a” and “an” refer to one or to more thanone (e.g., to at least one) of the grammatical object of the article.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or”, unless context clearly indicates otherwise.

“About” and “approximately” shall generally mean an acceptable degree oferror for the quantity measured given the nature or precision of themeasurements. Exemplary degrees of error are within 20 percent (%),typically, within 10%, and more typically, within 5% of a given value orrange of values.

The compositions and methods of the present invention encompasspolypeptides and nucleic acids having the sequences specified, orsequences substantially identical or similar thereto, e.g., sequences atleast 70%, 75%, 80%, 85%, 90%, 95% identical or higher to the sequencespecified. In the context of an amino acid sequence, the term“substantially identical” is used herein to refer to a first amino acidthat contains a sufficient or minimum number of amino acid residues thatare i) identical to, or ii) conservative substitutions of aligned aminoacid residues in a second amino acid sequence such that the first andsecond amino acid sequences can have a common structural domain and/orcommon functional activity. For example, amino acid sequences thatcontain a common structural domain having at least about 85%, 90%. 91%,92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a referencesequence, e.g., a sequence provided herein.

In the context of nucleotide sequence, the term “substantiallyidentical” is used herein to refer to a first nucleic acid sequence thatcontains a sufficient or minimum number of nucleotides that areidentical to aligned nucleotides in a second nucleic acid sequence suchthat the first and second nucleotide sequences encode a polypeptidehaving common functional activity, or encode a common structuralpolypeptide domain or a common functional polypeptide activity. Forexample, nucleotide sequences having at least about 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence,e.g., a sequence provided herein.

The term “functional variant” refers to polypeptides that have asubstantially identical amino acid sequence to the naturally-occurringsequence, or are encoded by a substantially identical nucleotidesequence, and are capable of having one or more activities of thenaturally-occurring sequence.

Calculations of homology or sequence identity between sequences (theterms are used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences, or of twonucleic acid sequences, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in one or both of a first and asecond amino acid or nucleic acid sequence for optimal alignment andnon-homologous sequences can be disregarded for comparison purposes). Ina preferred embodiment, the length of a reference sequence aligned forcomparison purposes is at least 30%, preferably at least 40%, morepreferably at least 50%, 60%, and even more preferably at least 70%,80%, 90%, 100% of the length of the reference sequence. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”).

The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunsch((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporatedinto the GAP program in the GCG software package (available athttp://www.gcg.com), using either a Blossum 62 matrix or a PAM250matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a lengthweight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, thepercent identity between two nucleotide sequences is determined usingthe GAP program in the GCG software package (available athttp://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Aparticularly preferred set of parameters (and the one that should beused unless otherwise specified) are a Blossum 62 scoring matrix with agap penalty of 12, a gap extend penalty of 4, and a frameshift gappenalty of 5.

The percent identity between two amino acid or nucleotide sequences canbe determined using the algorithm of E. Meyers and W. Miller ((1989)CABIOS, 4:11-17) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a“query sequence” to perform a search against public databases to, forexample, identify other family members or related sequences. Suchsearches can be performed using the NBLAST and XBLAST programs (version2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLASTnucleotide searches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to a nucleicacid (SEQ ID NO: 1) molecules of the invention. BLAST protein searchescan be performed with the XBLAST program, score=50, wordlength=3 toobtain amino acid sequences homologous to protein molecules of theinvention. To obtain gapped alignments for comparison purposes, GappedBLAST can be utilized as described in Altschul et al., (1997) NucleicAcids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

As used herein, the term “hybridizes under low stringency, mediumstringency, high stringency, or very high stringency conditions”describes conditions for hybridization and washing. Guidance forperforming hybridization reactions can be found in Current Protocols inMolecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which isincorporated by reference. Aqueous and nonaqueous methods are describedin that reference and either can be used. Specific hybridizationconditions referred to herein are as follows: 1) low stringencyhybridization conditions in 6× sodium chloride/sodium citrate (SSC) atabout 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at50° C. (the temperature of the washes can be increased to 55° C. for lowstringency conditions); 2) medium stringency hybridization conditions in6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1%SDS at 60° C.; 3) high stringency hybridization conditions in 6×SSC atabout 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65°C.; and preferably 4) very high stringency hybridization conditions are0.5M sodium phosphate, 7% SDS at 65° C., followed by one or more washesat 0.2×SSC, 1% SDS at 65° C. Very high stringency conditions (4) are thepreferred conditions and the ones that should be used unless otherwisespecified.

It is understood that the molecules of the present invention may haveadditional conservative or non-essential amino acid substitutions, whichdo not have a substantial effect on their functions.

The term “amino acid” is intended to embrace all molecules, whethernatural or synthetic, which include both an amino functionality and anacid functionality and capable of being included in a polymer ofnaturally-occurring amino acids. Exemplary amino acids includenaturally-occurring amino acids; analogs, derivatives and congenersthereof; amino acid analogs having variant side chains; and allstereoisomers of any of any of the foregoing. As used herein the term“amino acid” includes both the D- or L-optical isomers andpeptidomimetics.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a similar sidechain. Families of amino acid residues having similar side chains havebeen defined in the art. These families include amino acids with basicside chains (e.g., lysine, arginine, histidine), acidic side chains(e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine),nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,proline, phenylalanine, methionine, tryptophan), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine).

The terms “polypeptide”, “peptide” and “protein” (if single chain) areused interchangeably herein to refer to polymers of amino acids of anylength. The polymer may be linear or branched, it may comprise modifiedamino acids, and it may be interrupted by non-amino acids. The termsalso encompass an amino acid polymer that has been modified; forexample, disulfide bond formation, glycosylation, lipidation,acetylation, phosphorylation, or any other manipulation, such asconjugation with a labeling component. The polypeptide can be isolatedfrom natural sources, can be a produced by recombinant techniques from aeukaryotic or prokaryotic host, or can be a product of syntheticprocedures.

The terms “nucleic acid,” “nucleic acid sequence,” “nucleotidesequence,” or “polynucleotide sequence,” and “polynucleotide” are usedinterchangeably. They refer to a polymeric form of nucleotides of anylength, either deoxyribonucleotides or ribonucleotides, or analogsthereof. The polynucleotide may be either single-stranded ordouble-stranded, and if single-stranded may be the coding strand ornon-coding (antisense) strand. A polynucleotide may comprise modifiednucleotides, such as methylated nucleotides and nucleotide analogs. Thesequence of nucleotides may be interrupted by non-nucleotide components.A polynucleotide may be further modified after polymerization, such asby conjugation with a labeling component. The nucleic acid may be arecombinant polynucleotide, or a polynucleotide of genomic, cDNA,semisynthetic, or synthetic origin which either does not occur in natureor is linked to another polynucleotide in a nonnatural arrangement.

The term “isolated,” as used herein, refers to material that is removedfrom its original or native environment (e.g., the natural environmentif it is naturally occurring). For example, a naturally-occurringpolynucleotide or polypeptide present in a living animal is notisolated, but the same polynucleotide or polypeptide, separated by humanintervention from some or all of the co-existing materials in thenatural system, is isolated. Such polynucleotides could be part of avector and/or such polynucleotides or polypeptides could be part of acomposition, and still be isolated in that such vector or composition isnot part of the environment in which it is found in nature.

Various aspects of the invention are described in further detail below.Additional definitions are set out throughout the specification.

Antibody Molecules

In one embodiment, the antibody molecule binds to a mammalian, e.g.,human, LAG-3. For example, the antibody molecule binds specifically toan epitope, e.g., linear or conformational epitope, (e.g., an epitope asdescribed herein) on LAG-3. In some embodiments, the antibody moleculebinds to one or more extracellular Ig-like domains of LAG-3, e.g., thefirst, second, third or fourth extracellular Ig-like domain of LAG-3.

As used herein, the term “antibody molecule” refers to a protein, e.g.,an immunoglobin chain or fragment thereof, comprising at least oneimmunoglobulin variable domain sequence. The term “antibody molecule”includes, for example, a monoclonal antibody (including a full lengthantibody which has an immunoglobulin Fc region). In an embodiment, anantibody molecule comprises a full length antibody, or a full lengthimmunoglobin chain. In an embodiment, an antibody molecule comprises anantigen binding or functional fragment of a full length antibody, or afull length immunoglobulin chain.

In an embodiment, an antibody molecule is a monospecific antibodymolecule and binds a single epitope. E.g., a monospecific antibodymolecule having a plurality of immunoglobulin variable domain sequences,each of which binds the same epitope.

In an embodiment an antibody molecule is a multispecific antibodymolecule, e.g., it comprises a plurality of immunoglobulin variabledomains sequences, wherein a first immunoglobulin variable domainsequence of the plurality has binding specificity for a first epitopeand a second immunoglobulin variable domain sequence of the pluralityhas binding specificity for a second epitope. In an embodiment the firstand second epitopes are on the same antigen, e.g., the same protein (orsubunit of a multimeric protein). In an embodiment the first and secondepitopes overlap. In an embodiment the first and second epitopes do notoverlap. In an embodiment the first and second epitopes are on differentantigens, e.g., the different proteins (or different subunits of amultimeric protein). In an embodiment a multispecific antibody moleculecomprises a third, fourth or fifth immunoglobulin variable domain. In anembodiment, a multispecific antibody molecule is a bispecific antibodymolecule, a trispecific antibody molecule, or tetraspecific antibodymolecule,

In an embodiment a multispecific antibody molecule is a bispecificantibody molecule. A bispecific antibody has specificity for no morethan two antigens. A bispecific antibody molecule is characterized by afirst immunoglobulin variable domain sequence which has bindingspecificity for a first epitope and a second immunoglobulin variabledomain sequence that has binding specificity for a second epitope. In anembodiment the first and second epitopes are on the same antigen, e.g.,the same protein (or subunit of a multimeric protein). In an embodimentthe first and second epitopes overlap. In an embodiment the first andsecond epitopes do not overlap. In an embodiment the first and secondepitopes are on different antigens, e.g., the different proteins (ordifferent subunits of a multimeric protein). In an embodiment abispecific antibody molecule comprises a heavy chain variable domainsequence and a light chain variable domain sequence which have bindingspecificity for a first epitope and a heavy chain variable domainsequence and a light chain variable domain sequence which have bindingspecificity for a second epitope. In an embodiment a bispecific antibodymolecule comprises a half antibody having binding specificity for afirst epitope and a half antibody having binding specificity for asecond epitope. In an embodiment a bispecific antibody moleculecomprises a half antibody, or fragment thereof, having bindingspecificity for a first epitope and a half antibody, or fragmentthereof, having binding specificity for a second epitope. In anembodiment a bispecific antibody molecule comprises a scFv, or fragmentthereof, have binding specificity for a first epitope and a scFv, orfragment thereof, have binding specificity for a second epitope. In anembodiment, the first epitope is located on LAG-3 and the second epitopeis located on a PD-1, TIM-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5),PD-L1, or PD-L2.

In an embodiment, an antibody molecule comprises a diabody, and asingle-chain molecule, as well as an antigen-binding fragment of anantibody (e.g., Fab, F(ab′)₂, and Fv). For example, an antibody moleculecan include a heavy (H) chain variable domain sequence (abbreviatedherein as VH), and a light (L) chain variable domain sequence(abbreviated herein as VL). In an embodiment an antibody moleculecomprises or consists of a heavy chain and a light chain (referred toherein as a half antibody. In another example, an antibody moleculeincludes two heavy (H) chain variable domain sequences and two light (L)chain variable domain sequence, thereby forming two antigen bindingsites, such as Fab, Fab′, F(ab′)₂, Fc, Fd, Fd′, Fv, single chainantibodies (scFv for example), single variable domain antibodies,diabodies (Dab) (bivalent and bispecific), and chimeric (e.g.,humanized) antibodies, which may be produced by the modification ofwhole antibodies or those synthesized de novo using recombinant DNAtechnologies. These functional antibody fragments retain the ability toselectively bind with their respective antigen or receptor. Antibodiesand antibody fragments can be from any class of antibodies including,but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass(e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. The a preparation ofantibody molecules can be monoclonal or polyclonal. An antibody moleculecan also be a human, humanized, CDR-grafted, or in vitro generatedantibody. The antibody can have a heavy chain constant region chosenfrom, e.g., IgG, IgG2, IgG3, or IgG4. The antibody can also have a lightchain chosen from, e.g., kappa or lambda. The term “immunoglobulin” (Ig)is used interchangeably with the term “antibody” herein.

Examples of antigen-binding fragments of an antibody molecule include:(i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CLand CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprisingtwo Fab fragments linked by a disulfide bridge at the hinge region;(iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fvfragment consisting of the VL and VH domains of a single arm of anantibody, (v) a diabody (dAb) fragment, which consists of a VH domain;(vi) a camelid or camelized variable domain; (vii) a single chain Fv(scFv), see e.g., Bird et al. (1988) Science 242:423-426; and Huston etal. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) a singledomain antibody. These antibody fragments are obtained usingconventional techniques known to those with skill in the art, and thefragments are screened for utility in the same manner as are intactantibodies.

The term “antibody” includes intact molecules as well as functionalfragments thereof. Constant regions of the antibodies can be altered,e.g., mutated, to modify the properties of the antibody (e.g., toincrease or decrease one or more of: Fc receptor binding, antibodyglycosylation, the number of cysteine residues, effector cell function,or complement function).

Antibodies of the present invention can also be single domainantibodies. Single domain antibodies can include antibodies whosecomplementary determining regions are part of a single domainpolypeptide. Examples include, but are not limited to, heavy chainantibodies, antibodies naturally devoid of light chains, single domainantibodies derived from conventional 4-chain antibodies, engineeredantibodies and single domain scaffolds other than those derived fromantibodies. Single domain antibodies may be any of the art, or anyfuture single domain antibodies. Single domain antibodies may be derivedfrom any species including, but not limited to mouse, human, camel,llama, fish, shark, goat, rabbit, and bovine. According to anotheraspect of the invention, a single domain antibody is a naturallyoccurring single domain antibody known as heavy chain antibody devoid oflight chains. Such single domain antibodies are disclosed in WO94/04678, for example. For clarity reasons, this variable domain derivedfrom a heavy chain antibody naturally devoid of light chain is knownherein as a VHH or nanobody to distinguish it from the conventional VHof four chain immunoglobulins. Such a VHH molecule can be derived fromantibodies raised in Camelidae species, for example in camel, llama,dromedary, alpaca and guanaco. Other species besides Camelidae mayproduce heavy chain antibodies naturally devoid of light chain; suchVHHs are within the scope of the invention.

The VH and VL regions can be subdivided into regions ofhypervariability, termed “complementarity determining regions” (CDR),interspersed with regions that are more conserved, termed “frameworkregions” (FR or FW). The extent of the framework region and CDRs hasbeen precisely defined by a number of methods (see, Kabat, E. A., et al.(1991) Sequences of Proteins of Immunological Interest, Fifth Edition,U.S. Department of Health and Human Services, NIH Publication No.91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and theAbM definition used by Oxford Molecular's AbM antibody modelingsoftware. See, generally, e.g., Protein Sequence and Structure Analysisof Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.:Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg).

The terms “complementarity determining region,” and “CDR,” as usedherein refer to the sequences of amino acids within antibody variableregions which confer antigen specificity and binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region(LCDR1, LCDR2, LCDR3).

The precise amino acid sequence boundaries of a given CDR can bedetermined using any of a number of well-known schemes, including thosedescribed by Kabat et al. (1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (“Kabat” numbering scheme),Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numberingscheme). As used herein, the CDRs defined according the “Chothia” numberscheme are also sometimes referred to as “hypervariable loops.”

For example, under Kabat, the CDR amino acid residues in the heavy chainvariable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3); and the CDR amino acid residues in the light chainvariable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acidresidues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96(LCDR3). By combining the CDR definitions of both Kabat and Chothia, theCDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56(LCDR2), and 89-97 (LCDR3) in human VL.

Generally, unless specifically indicated, the anti-LAG-3 antibodymolecules can include any combination of one or more Kabat CDRs and/orChothia hypervariable loops, e.g., described in Table 1. In oneembodiment, the following definitions are used for the anti-LAG-3antibody molecules described in Table 1: HCDR1 according to the combinedCDR definitions of both Kabat and Chothia, and HCCDRs 2-3 and LCCDRs 1-3according the CDR definition of Kabat. Under all definitions, each VHand VL typically includes three CDRs and four FRs, arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4.

As used herein, an “immunoglobulin variable domain sequence” refers toan amino acid sequence which can form the structure of an immunoglobulinvariable domain. For example, the sequence may include all or part ofthe amino acid sequence of a naturally-occurring variable domain. Forexample, the sequence may or may not include one, two, or more N- orC-terminal amino acids, or may include other alterations that arecompatible with formation of the protein structure.

The term “antigen-binding site” refers to the part of an antibodymolecule that comprises determinants that form an interface that bindsto the LAG-3 polypeptide, or an epitope thereof. With respect toproteins (or protein mimetics), the antigen-binding site typicallyincludes one or more loops (of at least four amino acids or amino acidmimics) that form an interface that binds to the LAG-3 polypeptide.Typically, the antigen-binding site of an antibody molecule includes atleast one or two CDRs and/or hypervariable loops, or more typically atleast three, four, five or six CDRs and/or hypervariable loops.

The terms “compete” or “cross-compete” are used interchangeably hereinto refer to the ability of an antibody molecule to interfere withbinding of an anti-LAG-3 antibody molecule, e.g., an anti-LAG-3 antibodymolecule provided herein, to a target, e.g., human LAG-3. Theinterference with binding can be direct or indirect (e.g., through anallosteric modulation of the antibody molecule or the target). Theextent to which an antibody molecule is able to interfere with thebinding of another antibody molecule to the target, and thereforewhether it can be said to compete, can be determined using a competitionbinding assay, for example, a FACS assay, an ELISA or BIACORE assay. Insome embodiments, a competition binding assay is a quantitativecompetition assay. In some embodiments, a first anti-LAG-3 antibodymolecule is said to compete for binding to the target with a secondanti-LAG-3 antibody molecule when the binding of the first antibodymolecule to the target is reduced by 10% or more, e.g., 20% or more, 30%or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% ormore, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more,95% or more, 98% or more, 99% or more in a competition binding assay(e.g., a competition assay described herein).

As used herein, the term “epitope” refers to the moieties of an antigen(e.g., human LAG-3) that specifically interact with an antibodymolecule. Such moieties, referred to herein as epitopic determinants,typically comprise, or are part of, elements such as amino acid sidechains or sugar side chains. An epitopic determinate can be defined bymethods known in the art or disclosed herein, e.g., by crystallographyor by hydrogen-deuterium exchange. At least one or some of the moietieson the antibody molecule, that specifically interact with an epitopicdeterminant, are typically located in a CDR(s). Typically an epitope hasa specific three dimensional structural characteristics. Typically anepitope has specific charge characteristics. Some epitopes are linearepitopes while others are conformational epitopes.

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope. Amonoclonal antibody can be made by hybridoma technology or by methodsthat do not use hybridoma technology (e.g., recombinant methods).

An “effectively human” protein is a protein that does not evoke aneutralizing antibody response, e.g., the human anti-murine antibody(HAMA) response. HAMA can be problematic in a number of circumstances,e.g., if the antibody molecule is administered repeatedly, e.g., intreatment of a chronic or recurrent disease condition. A HAMA responsecan make repeated antibody administration potentially ineffectivebecause of an increased antibody clearance from the serum (see, e.g.,Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and alsobecause of potential allergic reactions (see, e.g., LoBuglio et al.,Hybridoma, 5:5117-5123 (1986)).

The antibody molecule can be a polyclonal or a monoclonal antibody. Inother embodiments, the antibody can be recombinantly produced, e.g.,produced by phage display or by combinatorial methods.

Phage display and combinatorial methods for generating antibodies areknown in the art (as described in, e.g., Ladner et al. U.S. Pat. No.5,223,409; Kang et al. International Publication No. WO 92/18619; Doweret al. International Publication No. WO 91/17271; Winter et al.International Publication WO 92/20791; Markland et al. InternationalPublication No. WO 92/15679; Breitling et al. International PublicationWO 93/01288; McCafferty et al. International Publication No. WO92/01047; Garrard et al. International Publication No. WO 92/09690;Ladner et al. International Publication No. WO 90/02809; Fuchs et al.(1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum AntibodHybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffthset al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al.(1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio/Technology9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; andBarbas et al. (1991) PNAS 88:7978-7982, the contents of all of which areincorporated by reference herein).

In one embodiment, the antibody is a fully human antibody (e.g., anantibody made in a mouse which has been genetically engineered toproduce an antibody from a human immunoglobulin sequence), or anon-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g.,monkey), camel antibody. Preferably, the non-human antibody is a rodent(mouse or rat antibody). Methods of producing rodent antibodies areknown in the art.

Human monoclonal antibodies can be generated using transgenic micecarrying the human immunoglobulin genes rather than the mouse system.Splenocytes from these transgenic mice immunized with the antigen ofinterest are used to produce hybridomas that secrete human mAbs withspecific affinities for epitopes from a human protein (see, e.g., Woodet al. International Application WO 91/00906, Kucherlapati et al. PCTpublication WO 91/10741; Lonberg et al. International Application WO92/03918; Kay et al. International Application 92/03917; Lonberg, N. etal. 1994 Nature 368:856-859; Green, L. L. et al. 1994 Nature Genet.7:13-21; Morrison, S. L. et al. 1994 Proc. Natl. Acad. Sci. USA81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon etal. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol21:1323-1326).

An antibody can be one in which the variable region, or a portionthereof, e.g., the CDRs, are generated in a non-human organism, e.g., arat or mouse. Chimeric, CDR-grafted, and humanized antibodies are withinthe invention. Antibodies generated in a non-human organism, e.g., a rator mouse, and then modified, e.g., in the variable framework or constantregion, to decrease antigenicity in a human are within the invention.

Chimeric antibodies can be produced by recombinant DNA techniques knownin the art (see Robinson et al., International Patent PublicationPCT/US86/02269; Akira, et al., European Patent Application 184,187;Taniguchi, M., European Patent Application 171,496; Morrison et al.,European Patent Application 173,494; Neuberger et al., InternationalApplication WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabillyet al., European Patent Application 125,023; Better et al. (1988 Science240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987,J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimuraet al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

A humanized or CDR-grafted antibody will have at least one or two butgenerally all three recipient CDRs (of heavy and or light immuoglobulinchains) replaced with a donor CDR. The antibody may be replaced with atleast a portion of a non-human CDR or only some of the CDRs may bereplaced with non-human CDRs. It is only necessary to replace the numberof CDRs required for binding of the humanized antibody to LAG-3.Preferably, the donor will be a rodent antibody, e.g., a rat or mouseantibody, and the recipient will be a human framework or a humanconsensus framework. Typically, the immunoglobulin providing the CDRs iscalled the “donor” and the immunoglobulin providing the framework iscalled the “acceptor.” In one embodiment, the donor immunoglobulin is anon-human (e.g., rodent). The acceptor framework is anaturally-occurring (e.g., a human) framework or a consensus framework,or a sequence about 85% or higher, preferably 90%, 95%, 99% or higheridentical thereto.

As used herein, the term “consensus sequence” refers to the sequenceformed from the most frequently occurring amino acids (or nucleotides)in a family of related sequences (See e.g., Winnaker, From Genes toClones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family ofproteins, each position in the consensus sequence is occupied by theamino acid occurring most frequently at that position in the family. Iftwo amino acids occur equally frequently, either can be included in theconsensus sequence. A “consensus framework” refers to the frameworkregion in the consensus immunoglobulin sequence.

An antibody can be humanized by methods known in the art (see e.g.,Morrison, S. L., 1985, Science 229:1202-1207, by Oi et al., 1986,BioTechniques 4:214, and by Queen et al. U.S. Pat. No. 5,585,089, U.S.Pat. No. 5,693,761 and U.S. Pat. No. 5,693,762, the contents of all ofwhich are hereby incorporated by reference).

Humanized or CDR-grafted antibodies can be produced by CDR-grafting orCDR substitution, wherein one, two, or all CDRs of an immunoglobulinchain can be replaced. See e.g., U.S. Pat. No. 5,225,539; Jones et al.1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidleret al. 1988 J. Immunol. 141:4053-4060; Winter U.S. Pat. No. 5,225,539,the contents of all of which are hereby expressly incorporated byreference. Winter describes a CDR-grafting method which may be used toprepare the humanized antibodies of the present invention (UK PatentApplication GB 2188638A, filed on Mar. 26, 1987; Winter U.S. Pat. No.5,225,539), the contents of which is expressly incorporated byreference.

Also within the scope of the invention are humanized antibodies in whichspecific amino acids have been substituted, deleted or added. Criteriafor selecting amino acids from the donor are described in U.S. Pat. No.5,585,089, e.g., columns 12-16 of U.S. Pat. No. 5,585,089, the e.g.,columns 12-16 of U.S. Pat. No. 5,585,089, the contents of which arehereby incorporated by reference. Other techniques for humanizingantibodies are described in Padlan et al. EP 519596 A1, published onDec. 23, 1992.

The antibody molecule can be a single chain antibody. A single-chainantibody (scFV) may be engineered (see, for example, Colcher, D. et al.(1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin CancerRes 2:245-52). The single chain antibody can be dimerized ormultimerized to generate multivalent antibodies having specificities fordifferent epitopes of the same target protein.

In yet other embodiments, the antibody molecule has a heavy chainconstant region chosen from, e.g., the heavy chain constant regions ofIgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly,chosen from, e.g., the (e.g., human) heavy chain constant regions ofIgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody moleculehas a light chain constant region chosen from, e.g., the (e.g., human)light chain constant regions of kappa or lambda. The constant region canbe altered, e.g., mutated, to modify the properties of the antibody(e.g., to increase or decrease one or more of: Fc receptor binding,antibody glycosylation, the number of cysteine residues, effector cellfunction, and/or complement function). In one embodiment the antibodyhas: effector function; and can fix complement. In other embodiments theantibody does not; recruit effector cells; or fix complement. In anotherembodiment, the antibody has reduced or no ability to bind an Fcreceptor. For example, it is an isotype or subtype, fragment or othermutant, which does not support binding to an Fc receptor, e.g., it has amutagenized or deleted Fc receptor binding region.

Methods for altering an antibody constant region are known in the art.Antibodies with altered function, e.g., altered affinity for an effectorligand, such as FcR on a cell, or the C1 component of complement can beproduced by replacing at least one amino acid residue in the constantportion of the antibody with a different residue (see e.g., EP 388,151A1, U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the contents ofall of which are hereby incorporated by reference). Similar type ofalterations could be described which if applied to the murine, or otherspecies immunoglobulin would reduce or eliminate these functions.

An antibody molecule can be derivatized or linked to another functionalmolecule (e.g., another peptide or protein). As used herein, a“derivatized” antibody molecule is one that has been modified. Methodsof derivatization include but are not limited to the addition of afluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinityligand such as biotin. Accordingly, the antibody molecules of theinvention are intended to include derivatized and otherwise modifiedforms of the antibodies described herein, including immunoadhesionmolecules. For example, an antibody molecule can be functionally linked(by chemical coupling, genetic fusion, noncovalent association orotherwise) to one or more other molecular entities, such as anotherantibody (e.g., a bispecific antibody or a diabody), a detectable agent,a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptidethat can mediate association of the antibody or antibody portion withanother molecule (such as a streptavidin core region or a polyhistidinetag).

One type of derivatized antibody molecule is produced by crosslinkingtwo or more antibodies (of the same type or of different types, e.g., tocreate bispecific antibodies). Suitable crosslinkers include those thatare heterobifunctional, having two distinctly reactive groups separatedby an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimideester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkersare available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents with which an antibody molecule of theinvention may be derivatized (or labeled) to include fluorescentcompounds, various enzymes, prosthetic groups, luminescent materials,bioluminescent materials, fluorescent emitting metal atoms, e.g.,europium (Eu), and other anthanides, and radioactive materials(described below). Exemplary fluorescent detectable agents includefluorescein, fluorescein isothiocyanate, rhodamine,5dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and thelike. An antibody may also be derivatized with detectable enzymes, suchas alkaline phosphatase, horseradish peroxidase, β-galactosidase,acetylcholinesterase, glucose oxidase and the like. When an antibody isderivatized with a detectable enzyme, it is detected by addingadditional reagents that the enzyme uses to produce a detectablereaction product. For example, when the detectable agent horseradishperoxidase is present, the addition of hydrogen peroxide anddiaminobenzidine leads to a colored reaction product, which isdetectable. An antibody molecule may also be derivatized with aprosthetic group (e.g., streptavidin/biotin and avidin/biotin). Forexample, an antibody may be derivatized with biotin, and detectedthrough indirect measurement of avidin or streptavidin binding. Examplesof suitable fluorescent materials include umbelliferone, fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; an example of aluminescent material includes luminol; and examples of bioluminescentmaterials include luciferase, luciferin, and aequorin.

Labeled antibody molecule can be used, for example, diagnosticallyand/or experimentally in a number of contexts, including (i) to isolatea predetermined antigen by standard techniques, such as affinitychromatography or immunoprecipitation; (ii) to detect a predeterminedantigen (e.g., in a cellular lysate or cell supernatant) in order toevaluate the abundance and pattern of expression of the protein; (iii)to monitor protein levels in tissue as part of a clinical testingprocedure, e.g., to determine the efficacy of a given treatment regimen.

An antibody molecules may be conjugated to another molecular entity,typically a label or a therapeutic (e.g., a cytotoxic or cytostatic)agent or moiety. Radioactive isotopes can be used in diagnostic ortherapeutic applications. Radioactive isotopes that can be coupled tothe anti-PSMA antibodies include, but are not limited to α-, β-, orγ-emitters, or β- and γ-emitters. Such radioactive isotopes include, butare not limited to iodine (¹³¹I or ¹²⁵I), yttrium (⁹⁰Y), lutetium(¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine (²¹¹At), rhenium(¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), indium (¹¹¹In), technetium (⁹⁹mTc),phosphorus (³²P), rhodium (¹⁸⁸Rh), sulfur (³⁵S), carbon (¹⁴C), tritium(³H), chromium (⁵¹Cr), chlorine (³⁶Cl), cobalt (⁵⁷Co or ⁵⁸Co), iron(⁵⁹Fe), selenium (⁷⁵Se), or gallium (⁶⁷Ga). Radioisotopes useful astherapeutic agents include yttrium (⁹⁰Y), lutetium (¹⁷⁷Lu), actinium(²²⁵Ac), praseodymium, astatine (²¹¹At), rhenium (¹⁸⁶Re), bismuth (²¹²Bior ²¹³Bi), and rhodium (¹⁸⁸Rh). Radioisotopes useful as labels, e.g.,for use in diagnostics, include iodine (¹³¹I or ¹²⁵I), indium (¹¹¹In),technetium (⁹⁹mTc), phosphorus (³²P), carbon (¹⁴C), and tritium (³H), orone or more of the therapeutic isotopes listed above.

The invention provides radiolabeled antibody molecules and methods oflabeling the same. In one embodiment, a method of labeling an antibodymolecule is disclosed. The method includes contacting an antibodymolecule, with a chelating agent, to thereby produce a conjugatedantibody. The conjugated antibody is radiolabeled with a radioisotope,e.g., ¹¹¹Indium, ⁹⁰Yttrium and ¹⁷⁷Lutetium, to thereby produce a labeledantibody molecule.

As is discussed above, the antibody molecule can be conjugated to atherapeutic agent. Therapeutically active radioisotopes have alreadybeen mentioned. Examples of other therapeutic agents include taxol,cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin,etoposide, tenoposide, vincristine, vinblastine, colchicine,doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids,procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids,e.g., maytansinol (see U.S. Pat. No. 5,208,020), CC-1065 (see U.S. Pat.Nos. 5,475,092, 5,585,499, 5,846, 545) and analogs or homologs thereof.Therapeutic agents include, but are not limited to, antimetabolites(e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine,5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine,thioepa chlorambucil, CC-1065, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclinies (e.g., daunorubicin (formerly daunomycin)and doxorubicin), antibiotics (e.g., dactinomycin (formerlyactinomycin), bleomycin, mithramycin, and anthramycin (AMC)), andanti-mitotic agents (e.g., vincristine, vinblastine, taxol andmaytansinoids).

In one aspect, the invention features a method of providing a targetbinding molecule that specifically binds to a LAG-3 receptor. Forexample, the target binding molecule is an antibody molecule. The methodincludes: providing a target protein that comprises at least a portionof non-human protein, the portion being homologous to (at least 70, 75,80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical to) a correspondingportion of a human target protein, but differing by at least one aminoacid (e.g., at least one, two, three, four, five, six, seven, eight, ornine amino acids); obtaining an antibody molecule that specificallybinds to the antigen; and evaluating efficacy of the binding agent inmodulating activity of the target protein. The method can furtherinclude administering the binding agent (e.g., antibody molecule) or aderivative (e.g., a humanized antibody molecule) to a human subject.

This invention provides an isolated nucleic acid molecule encoding theabove antibody molecule, vectors and host cells thereof. The nucleicacid molecule includes but is not limited to RNA, genomic DNA and cDNA.

In certain embodiments, the antibody molecule is a multi-specific (e.g.,a bispecific or a trispecific) antibody molecule. Protocols forgenerating bispecific or heterodimeric antibody molecules are known inthe art; including but not limited to, for example, the “knob in a hole”approach described in, e.g., U.S. Pat. No. 5,731,168; the electrostaticsteering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905and WO 2010/129304; Strand Exchange Engineered Domains (SEED)heterodimer formation as described in, e.g., WO 07/110205; Fab armexchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO2013/060867; double antibody conjugate, e.g., by antibody cross-linkingto generate a bi-specific structure using a heterobifunctional reagenthaving an amine-reactive group and a sulfhydryl reactive group asdescribed in, e.g., U.S. Pat. No. 4,433,059; bispecific antibodydeterminants generated by recombining half antibodies (heavy-light chainpairs or Fabs) from different antibodies through cycle of reduction andoxidation of disulfide bonds between the two heavy chains, as describedin, e.g., U.S. Pat. No. 4,444,878; trifunctional antibodies, e.g., threeFab′ fragments cross-linked through sulfhydryl reactive groups, asdescribed in, e.g., U.S. Pat. No. 5,273,743; biosynthetic bindingproteins, e.g., pair of scFvs cross-linked through C-terminal tailspreferably through disulfide or amine-reactive chemical cross-linking,as described in, e.g., U.S. Pat. No. 5,534,254; bifunctional antibodies,e.g., Fab fragments with different binding specificities dimerizedthrough leucine zippers (e.g., c-fos and c-jun) that have replaced theconstant domain, as described in, e.g., U.S. Pat. No. 5,582,996;bispecific and oligospecific mono- and oligovalent receptors, e.g.,VH—CH1 regions of two antibodies (two Fab fragments) linked through apolypeptide spacer between the CH1 region of one antibody and the VHregion of the other antibody typically with associated light chains, asdescribed in, e.g., U.S. Pat. No. 5,591,828; bispecific DNA-antibodyconjugates, e.g., crosslinking of antibodies or Fab fragments through adouble stranded piece of DNA, as described in, e.g., U.S. Pat. No.5,635,602; bispecific fusion proteins, e.g., an expression constructcontaining two scFvs with a hydrophilic helical peptide linker betweenthem and a full constant region, as described in, e.g., U.S. Pat. No.5,637,481; multivalent and multispecific binding proteins, e.g., dimerof polypeptides having first domain with binding region of Ig heavychain variable region, and second domain with binding region of Ig lightchain variable region, generally termed diabodies (higher orderstructures are also encompassed creating for bispecific, trispecific, ortetraspecific molecules, as described in, e.g., U.S. Pat. No. 5,837,242;minibody constructs with linked VL and VH chains further connected withpeptide spacers to an antibody hinge region and CH3 region, which can bedimerized to form bispecific/multivalent molecules, as described in,e.g., U.S. Pat. No. 5,837,821; VH and VL domains linked with a shortpeptide linker (e.g., 5 or 10 amino acids) or no linker at all in eitherorientation, which can form dimers to form bispecific diabodies; trimersand tetramers, as described in, e.g., U.S. Pat. No. 5,844,094; String ofVH domains (or VL domains in family members) connected by peptidelinkages with crosslinkable groups at the C-terminus further associatedwith VL domains to form a series of FVs (or scFvs), as described in,e.g., U.S. Pat. No. 5,864,019; and single chain binding polypeptideswith both a VH and a VL domain linked through a peptide linker arecombined into multivalent structures through non-covalent or chemicalcrosslinking to form, e.g., homobivalent, heterobivalent, trivalent, andtetravalent structures using both scFV or diabody type format, asdescribed in, e.g., U.S. Pat. No. 5,869,620. Additional exemplarymultispecific and bispecific molecules and methods of making the sameare found, for example, in U.S. Pat. No. 5,910,573, U.S. Pat. No.5,932,448, U.S. Pat. No. 5,959,083, U.S. Pat. No. 5,989,830, U.S. Pat.No. 6,005,079, U.S. Pat. No. 6,239,259, U.S. Pat. No. 6,294,353, U.S.Pat. No. 6,333,396, U.S. Pat. No. 6,476,198, U.S. Pat. No. 6,511,663,U.S. Pat. No. 6,670,453, U.S. Pat. No. 6,743,896, U.S. Pat. No.6,809,185, U.S. Pat. No. 6,833,441, U.S. Pat. No. 7,129,330, U.S. Pat.No. 7,183,076, U.S. Pat. No. 7,521,056, U.S. Pat. No. 7,527,787, U.S.Pat. No. 7,534,866, U.S. Pat. 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The contents of theabove-referenced applications are incorporated herein by reference intheir entireties.

In other embodiments, the anti-LAG-3 antibody molecule (e.g., amonospecific, bispecific, or multispecific antibody molecule) iscovalently linked, e.g., fused, to another partner e.g., a protein e.g.,one, two or more cytokines, e.g., as a fusion molecule for example afusion protein. In other embodiments, the fusion molecule comprises oneor more proteins, e.g., one, two or more cytokines. In one embodiment,the cytokine is an interleukin (IL) chosen from one, two, three or moreof IL-1, IL-2, IL-12, IL-15 or IL-21. In one embodiment, a bispecificantibody molecule has a first binding specificity to a first target(e.g., to LAG-3), a second binding specificity to a second target (e.g.,PD-1, TIM-3, or PD-L1), and is optionally linked to an interleukin(e.g., IL-12) domain e.g., full length IL-12 or a portion thereof.

A “fusion protein” and a “fusion polypeptide” refer to a polypeptidehaving at least two portions covalently linked together, where each ofthe portions is a polypeptide having a different property. The propertymay be a biological property, such as activity in vitro or in vivo. Theproperty can also be simple chemical or physical property, such asbinding to a target molecule, catalysis of a reaction, etc. The twoportions can be linked directly by a single peptide bond or through apeptide linker, but are in reading frame with each other.

This invention provides an isolated nucleic acid molecule encoding theabove antibody molecules, vectors and host cells thereof. The nucleicacid molecule includes but is not limited to RNA, genomic DNA and cDNA.

Exemplary Anti-LAG-3 Antibody Molecules

In certain embodiments, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12.

In other embodiments, the anti-LAG-3 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) comprising a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15.

In embodiments of the aforesaid antibody molecules, the VHCDR1 comprisesthe amino acid sequence of SEQ ID NO: 1. In other embodiments, theVHCDR1 comprises the amino acid sequence of SEQ ID NO: 4. In yet otherembodiments, the VHCDR1 amino acid sequence of SEQ ID NO: 286.

In embodiments, the aforesaid antibody molecules have a heavy chainvariable region comprising at least one framework (FW) region comprisingthe amino acid sequence of any of SEQ ID NOs: 187, 190, 194, 196, 198,202, 206, 208, 210, 212, 217, 219, or 221, or an amino acid sequence atleast 90% identical thereto, or having no more than two amino acidsubstitutions, insertions or deletions compared to the amino acidsequence of any of SEQ ID NOs: 187, 190, 194, 196, 198, 202, 206, 208,210, 212, 217, 219, or 221.

In other embodiments, the aforesaid antibody molecules have a heavychain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 187, 190, 194,196, 198, 202, 206, 208, 210, 212, 217, 219, or 221.

In yet other embodiments, the aforesaid antibody molecules have a heavychain variable region comprising at least two, three, or four frameworkregions comprising the amino acid sequences of any of SEQ ID NOs: 187,190, 194, 196, 198, 202, 206, 208, 210, 212, 217, 219, or 221.

In other embodiments, the aforesaid antibody molecules comprise a VHFW1amino acid sequence of SEQ ID NO: 187, 190, 194, or 196, a VHFW2 aminoacid sequence of SEQ ID NO: 198, 202, 206, or 208, and a VHFW3 aminoacid sequence of SEQ ID NO: 210, 212, 217, or 219, and, optionally,further comprising a VHFW4 amino acid sequence of SEQ ID NO: 221.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 226, 230, 232,234, 236, 238, 240, 244, 246, 248, 252, 255, 259, 261, 265, 267, 269, or271, or an amino acid sequence at least 90% identical thereto, or havingno more than two amino acid substitutions, insertions or deletionscompared to the amino acid sequence of any of 226, 230, 232, 234, 236,238, 240, 244, 246, 248, 252, 255, 259, 261, 265, 267, 269, or 271.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 226, 230, 232,234, 236, 238, 240, 244, 246, 248, 252, 255, 259, 261, 265, 267, 269, or271.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least two, three, or four frameworkregions comprising the amino acid sequences of any of SEQ ID NOs: 226,230, 232, 234, 236, 238, 240, 244, 246, 248, 252, 255, 259, 261, 265,267, 269, or 271.

In other embodiments, the aforesaid antibody molecules comprise a VLFW1amino acid sequence of SEQ ID NO: 226, 230, 232, 234, 236, or 2385, aVLFW2 amino acid sequence of SEQ ID NO: 240, 244, 246, or 248, and aVLFW3 amino acid sequence of SEQ ID NO: 252, 255, 259, 261, 265, 267, or269, and, optionally, further comprising a VLFW4 amino acid sequence ofSEQ ID NO: 271.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising an amino acid sequence at least 85%identical to any of SEQ ID NOs: 8, 28, 64, 68, 72, 76, 80, 100, 104, or108.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:8, 28, 64, 68, 72, 76, 80, 100, 104, or 108.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising an amino acid sequence at least 85%identical to any of SEQ ID NOs: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88,92, or 96.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92, or 96.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:8.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 18.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:68.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 70.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:72.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 74.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:76.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 78.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:80.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 82.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:100.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 102 or SEQ ID NO:113.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:104.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 106.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 122.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:108.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 110.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 134.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:32.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:36.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:40.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 42.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:44.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 46.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:48.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 50.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:52.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 54.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:56.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:60.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:84.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:88.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 90.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:92.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 94.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:96.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 98.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 32.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 36.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 40.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 48.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 52.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO: 104; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 36.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO: 104; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 40.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO: 104; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO: 104; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:68 or SEQ ID NO: 108; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 36.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:72 or SEQ ID NO: 8; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 40.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:72 or SEQ ID NO: 8; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:76 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:80 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 84.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 88.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:28 or SEQ ID NO: 100; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 92.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:64 or SEQ ID NO: 104; and a light chain variable domain comprising theamino acid sequence of SEQ ID NO: 96.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:34.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:42.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:46.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:50.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:54.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:58.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:62.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO:106; and a light chain comprising the amino acid sequence of SEQ ID NO:38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO:106; and a light chain comprising the amino acid sequence of SEQ ID NO:42.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO:106; and a light chain comprising the amino acid sequence of SEQ ID NO:58.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO:106; and a light chain comprising the amino acid sequence of SEQ ID NO:62.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 70 or SEQ ID NO:110; and a light chain comprising the amino acid sequence of SEQ ID NO:38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO:18; and a light chain comprising the amino acid sequence of SEQ ID NO:42.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 74 or SEQ ID NO:18; and a light chain comprising the amino acid sequence of SEQ ID NO:62.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 78 and a lightchain comprising the amino acid sequence of SEQ ID NO: 62.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 82 and a lightchain comprising the amino acid sequence of SEQ ID NO: 86.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:94.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO:106; and a light chain comprising the amino acid sequence of SEQ ID NO:98.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 113 and a lightchain comprising the amino acid sequence of SEQ ID NO: 34.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 113 and a lightchain comprising the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 122 and a lightchain comprising the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 122 and a lightchain comprising the amino acid sequence of SEQ ID NO: 58.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 134 and a lightchain comprising the amino acid sequence of SEQ ID NO: 38.

In other embodiments, the aforesaid antibody molecules are chosen from aFab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).

In other embodiments, the aforesaid antibody molecules comprise a heavychain constant region selected from IgG1, IgG2, IgG3, and IgG4.

In other embodiments, the aforesaid antibody molecules comprise a lightchain constant region chosen from the light chain constant regions ofkappa or lambda.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG4 heavy chain constant region with a mutation at position 228according to EU numbering or position 108 of SEQ ID NO: 275 or 277 and akappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG4 heavy chain constant region with a Serine to Proline mutation atposition 228 according to EU numbering or position 108 of SEQ ID NO: 275or 277 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with an Asparagine to Alanine mutationat position 297 according to EU numbering or position 180 of SEQ ID NO:279 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with an Aspartate to Alanine mutationat position 265 according to EU numbering or position 148, and Prolineto Alanine mutation at position 329 according to EU numbering orposition 212 of SEQ ID NO: 280 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with a Leucine to Alanine mutation atposition 234 according to EU numbering or position 117 and Leucine toAlanine mutation at position 235 according to EU numbering or position118 of SEQ ID NO: 281 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules are capable ofbinding to human LAG-3 with a dissociation constant (K_(D)) of less thanabout 0.2 nM.

In some embodiments, the aforesaid antibody molecules bind to humanLAG-3 with a K_(D) of less than about 0.2 nM, 0.15 nM, 0.1 nM, 0.05 nM,or 0.02 nM, e.g., about 0.05 nM to 0.15 nM, e.g., about 0.11 nM, e.g.,as measured by a Biacore method.

In other embodiments, the aforesaid antibody molecules bind tocynomolgus LAG-3 with a K_(D) of less than about 0.2 nM, 0.15 nM, 0.1nM, 0.05 nM, or 0.02 nM, e.g., about 0.05 nM to 0.15 nM, e.g., asmeasured by a Biacore method.

In certain embodiments, the aforesaid antibody molecules bind to bothhuman LAG-3 and cynomolgus LAG-3 with similar K_(D), e.g., in the nMrange, e.g., as measured by a Biacore method. In some embodiments, theaforesaid antibody molecules bind to a human LAG-3-Ig fusion proteinwith a K_(D) of less than about 0.5 nM, 0.2 nM, 0.1 nM, 0.05 nM, 0.025nM, or 0.01 nM, e.g., as measured by ELISA.

In some embodiments, the aforesaid antibody molecules bind to CHO cellsthat express human LAG-3 (e.g., human LAG-3-transfected CHO cells) witha K_(D) of less than about 4 nM, 2.5 nM, 2 nM, 1.5 nM, 1 nM, 0.75 nM,0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM, or 0.05 nM, e.g., about 2.3,1.92 nM or about 0.2 nM, e.g., as measured by FACS analysis.

In some embodiments, the aforesaid antibody molecules bind to human Tcells with a K_(D) of less than about 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM,0.1 nM, or 0.05 nM, e.g., about 0.26 nM, e.g., as measured by FACSanalysis.

In some embodiments, the aforesaid antibody molecules bind to cells thatexpress LAG-3 (e.g., human LAG-3-expressing 300.19 cells) with a K_(D)of less than about 20 nM, 15 nM, 10 nM, 5 nM, 2 nM, or 1 nM, e.g., about13.6 nM, e.g., as measured by FACS analysis.

In some embodiments, the aforesaid antibody molecules bind to cells thatexpress rhesus LAG-3 (e.g., cells transfected with rhesus LAG-3) with aK_(D) of less than about 15 nM, 10 nM, 9 nM, 8 nM, 6 nM, 5 nM, 2 nM, or1 nM, e.g., about 8.03 nM, e.g., as measured by FACS analysis.

In certain embodiments, the aforesaid antibody molecules are notcross-reactive with mouse LAG-3. In some embodiments, the aforesaidantibodies are not cross-reactive with rat LAG-3. In other embodiments,the aforesaid antibodies are cross-reactive with rhesus LAG-3. In someembodiments, the aforesaid antibodies are cross-reactive with rat LAG-3.For example, the cross-reactivity can be measured by a Biacore method ora binding assay using cells that expresses LAG-3 (e.g., humanLAG-3-expressing 300.19 cells).

In other embodiments, the aforesaid antibody molecules bind anextracellular Ig-like domain of LAG-3 (e.g., human LAG-3), e.g., any ofDomain 1 (D1), Domain 2 (D2), Domain 3 (D3), or Domain 4 (D4). In someembodiments, the aforesaid antibody molecules bind one or more aminoacid residues in D1. In some embodiments, the aforesaid antibodymolecules do not bind the extra loop of D1 or a fragment thereof (e.g.,as measured by a Biacore method or a FACS method). In some embodiments,the aforesaid antibodies do not bind D2. In some embodiments, theaforesaid antibody molecules bind both D1 and D2. In some embodiments,the aforesaid antibody molecules bind one or more amino acid residues inD1 and/or D2 that bind an MHC class II molecule. In other embodiments,the aforesaid antibody molecules are capable of reducing binding ofLAG-3 to a major histocompatibility (MHC) class II molecule, or a cellthat expresses an MHC class II molecule. In some embodiments, theaforesaid antibody molecules reduce (e.g., block) LAG-3-Ig binding to aMHC class II molecule, e.g., on Raji cells or Daudi cells, with an IC₅₀of less than about 10 nM, 8 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or 0.5 nM,e.g., between about 8 nM and about 10 nM or between about 2 nM and about3 nM, e.g., about 5.5 nM or about 2.3 nM.

In other embodiments, the aforesaid antibody molecules are capable ofenhancing an antigen-specific T cell response.

In embodiments, the antibody molecule is a monospecific antibodymolecule or a bispecific antibody molecule. In embodiments, the antibodymolecule has a first binding specificity for LAG-3 and a second bindingspecifity for PD-1, TIM-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5),PD-L1 or PD-L2. In embodiments, the antibody molecule comprises anantigen binding fragment of an antibody, e.g., a half antibody orantigen binding fragment of a half antibody.

In some embodiments, the aforesaid antibody molecules increase theexpression of IL-2 from cells activated by Staphylococcal enterotoxin B(SEB) (e.g., at 25 μg/mL) by at least about 2, 3, 4, 5-fold, e.g., about2 to 3-fold, compared to the expression of IL-2 when an isotype control(e.g., IgG4) is used, e.g., as measured in a SEB T cell activation assayor a human whole blood ex vivo assay.

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells stimulated by anti-CD3 (e.g., at 0.1μg/mL) by at least about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8-fold, e.g.,about 0.9 to 5.1-fold, e.g., about 3-fold, compared to the expression ofIFN-γ when an isotype control (e.g., IgG4) is used, e.g., as measured inan IFN-γ activity assay.

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells activated by SEB (e.g., at 3 pg/mL) byat least about 2, 3, 4, 5-fold, e.g., about 1.2 to 2-fold, e.g., about1.6-fold, compared to the expression of IFN-γ when an isotype control(e.g., IgG4) is used, e.g., as measured in an IFN-γ activity assay.

In some embodiments, the aforesaid antibody molecules do not increasethe expression of IL-2 or IFN-γ without T cell receptor activation (e.g.in the absence of SEB).

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells activated with an CMV peptide by atleast about 2, 3, 4, 5-fold, e.g., about 1.1 to 1.7-fold, e.g., about1.4-fold, compared to the expression of IFN-γ when an isotype control(e.g., IgG4) is used, e.g., as measured in an IFN-γ activity assay. Insome embodiments, the aforesaid antibody molecules increase theproliferation of CD8⁺ T cells activated with an CMV peptide by at leastabout 1, 2, 3, 4, 5-fold, e.g., about 1.5-fold, compared to theproliferation of CD8⁺ T cells when an isotype control (e.g., IgG4) isused, e.g., as measured by the percentage of CD8+ T cells that passedthrough at least n (e.g., n=2 or 4) cell divisions.

In certain embodiments, the aforesaid antibody molecules has a Cmaxbetween about 50 μg/mL and about 400 μg/mL, between about 100 μg/mL andabout 350 μg/mL, between about 150 μg/mL and about 300 μg/mL, or betweenabout 200 μg/mL and about 250 μg/mL, e.g., about 166 μg/mL, e.g., asmeasured in an animal.

In certain embodiments, the aforesaid antibody molecules has a T_(1/2)between about 50 hours and about 400 hours, between about 100 hours andabout 350 hours, between about 150 hours and about 300 hours, or betweenabout 200 hours and about 250 hours, e.g., about 231.9 hours, e.g., asmeasured in an animal.

In some embodiments, the aforesaid antibody molecules bind to LAG-3 witha Kd slower than 5×10⁻⁴, 1×10⁻⁴, 5×10⁻⁵, or 1×10⁻⁵ s⁻¹, e.g., about7×10⁻⁵ s⁻¹, e.g., as measured by a Biacore method. In some embodiments,the aforesaid antibodies bind to LAG-3 with a Ka faster than 1×10⁴,5×10⁴, 1×10⁵, 5×10⁵, or 1×10⁶ M⁻¹s⁻¹, e.g., about 6.41×10⁵ M⁻¹s⁻¹, e.g.,as measured by a Biacore method.

In another aspect, the invention provides an isolated nucleic acidmolecule encoding any of the aforesaid antibody molecules, vectors andhost cells thereof.

In one embodiment, the isolated nucleic acid encodes the antibody heavychain variable region or light chain variable region, or both, of anythe aforesaid antibody molecules.

In one embodiment, the isolated nucleic acid encodes heavy chain CDRs1-3, wherein said nucleic acid comprises a nucleotide sequence of SEQ IDNO: 140-144, 151-155, 162-166, 173-177, 184-186, or 287.

In another embodiment, the isolated nucleic acid encodes light chainCDRs 1-3, wherein said nucleic acid comprises a nucleotide sequence ofSEQ ID NO: 145-150, 156-161, 167-172, or 178-183.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain variable domain, wherein saidnucleotide sequence is at least 85% identical to any of SEQ ID NO: 9,29, 65, 69, 73, 77, 81, 101, 105, 109, 112, 121, 124, 125, 132, or 133.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain variable domain, wherein saidnucleotide sequence comprises any of SEQ ID NO: 9, 29, 65, 69, 73, 77,81, 101, 105, 109, 112, 121, 124, 125, 132, or 133.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain, wherein said nucleotidesequence is at least 85% identical to any of SEQ ID NO: 19, 31, 67, 71,75, 79, 83, 103, 107, 111, 114, 123, 126, 127, 135, or 136.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain, wherein said nucleotidesequence comprises any of SEQ ID NO: 19, 31, 67, 71, 75, 79, 83, 103,107, 111, 114, 123, 126, 127, 135, or 136.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain variable domain, wherein saidnucleotide sequence is at least 85% identical to any of SEQ ID NO: 33,37, 41, 45, 49, 53, 57, 61, 85, 89, 93, 97, 115, 118, 128, 129, or 137.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain variable domain, wherein saidnucleotide sequence comprises any of SEQ ID NO: 33, 37, 41, 45, 49, 53,57, 61, 85, 89, 93, 97, 115, 118, 128, 129, or 137.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain, wherein said nucleotidesequence is at least 85% identical to any of SEQ ID NO: 35, 39, 43, 47,51, 55, 59, 63, 87, 91, 95, 99, 117, 120, 130, 131, 138, or 139.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain, wherein said nucleotidesequence comprises any of SEQ ID NO: 35, 39, 43, 47, 51, 55, 59, 63, 87,91, 95, 99, 117, 120, 130, 131, 138, or 139.

In certain embodiments, one or more expression vectors and host cellscomprising the aforesaid nucleic acids are provided.

A method of producing an antibody molecule or fragment thereof,comprising culturing the host cell as described herein under conditionssuitable for gene expression is also provided.

Pharmaceutical Compositions and Kits

In another aspect, the present invention provides compositions, e.g.,pharmaceutically acceptable compositions, which include an antibodymolecule described herein, formulated together with a pharmaceuticallyacceptable carrier. As used herein, “pharmaceutically acceptablecarrier” includes any and all solvents, dispersion media, isotonic andabsorption delaying agents, and the like that are physiologicallycompatible. The carrier can be suitable for intravenous, intramuscular,subcutaneous, parenteral, rectal, spinal or epidermal administration(e.g., by injection or infusion).

The compositions of this invention may be in a variety of forms. Theseinclude, for example, liquid, semi-solid and solid dosage forms, such asliquid solutions (e.g., injectable and infusible solutions), dispersionsor suspensions, liposomes and suppositories. The preferred form dependson the intended mode of administration and therapeutic application.Typical preferred compositions are in the form of injectable orinfusible solutions. The preferred mode of administration is parenteral(e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In apreferred embodiment, the antibody is administered by intravenousinfusion or injection. In another preferred embodiment, the antibody isadministered by intramuscular or subcutaneous injection.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, epidural and intrasternal injection andinfusion.

Therapeutic compositions typically should be sterile and stable underthe conditions of manufacture and storage. The composition can beformulated as a solution, microemulsion, dispersion, liposome, or otherordered structure suitable to high antibody concentration. Sterileinjectable solutions can be prepared by incorporating the activecompound (i.e., antibody or antibody portion) in the required amount inan appropriate solvent with one or a combination of ingredientsenumerated above, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the active compoundinto a sterile vehicle that contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.The proper fluidity of a solution can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prolonged absorption of injectable compositions can be brought about byincluding in the composition an agent that delays absorption, forexample, monostearate salts and gelatin.

The antibody molecules can be administered by a variety of methods knownin the art, although for many therapeutic applications, the preferredroute/mode of administration is intravenous injection or infusion. Inone embodiment, the antibody molecule is administered by intravenousinfusion at a rate of more than 20 mg/min, e.g., 20-40 mg/min, andpreferably greater than or equal to 40 mg/min to reach a dose of about35 to 440 mg/m², preferably about 70 to 310 mg/m², and more preferably,about 110 to 130 mg/m². In another embodiment, the antibody molecule isadministered by intravenous infusion at a rate of less than 10 mg/min;preferably less than or equal to 5 mg/min to reach a dose of about 1 to100 mg/m², preferably about 5 to 50 mg/m², about 7 to 25 mg/m² and morepreferably, about 10 mg/m². As will be appreciated by the skilledartisan, the route and/or mode of administration will vary dependingupon the desired results. In certain embodiments, the active compoundmay be prepared with a carrier that will protect the compound againstrapid release, such as a controlled release formulation, includingimplants, transdermal patches, and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Many methods for the preparationof such formulations are patented or generally known to those skilled inthe art. See, e.g., Sustained and Controlled Release Drug DeliverySystems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, an antibody molecule can be orally administered,for example, with an inert diluent or an assimilable edible carrier. Thecompound (and other ingredients, if desired) may also be enclosed in ahard or soft shell gelatin capsule, compressed into tablets, orincorporated directly into the subject's diet. For oral therapeuticadministration, the compounds may be incorporated with excipients andused in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Toadminister a compound of the invention by other than parenteraladministration, it may be necessary to coat the compound with, orco-administer the compound with, a material to prevent its inactivation.Therapeutic compositions can also be administered with medical devicesknown in the art.

Dosage regimens are adjusted to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for thesubjects to be treated; each unit contains a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the active compound andthe particular therapeutic effect to be achieved, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

An exemplary, non-limiting range for a therapeutically orprophylactically effective amount of an antibody molecule is 0.1-30mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens ofthe anti-LAG-3 antibody molecule can be determined by a skilled artisan.In certain embodiments, the anti-LAG-3 antibody molecule is administeredby injection (e.g., subcutaneously or intravenously) at a dose of about1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20mg/kg, 15 to 25 mg/kg, or about 3 mg/kg. The dosing schedule can varyfrom e.g., once a week to once every 2, 3, or 4 weeks. In oneembodiment, the anti-LAG-3 antibody molecule is administered at a dosefrom about 10 to 20 mg/kg every other week. The antibody molecule can beadministered by intravenous infusion at a rate of more than 20 mg/min,e.g., 20-40 mg/min, and preferably greater than or equal to 40 mg/min toreach a dose of about 35 to 440 mg/m², preferably about 70 to 310 mg/m²,and more preferably, about 110 to 130 mg/m². In embodiments, theinfusion rate of about 110 to 130 mg/m² achieves a level of about 3mg/kg. In one embodiment, the anti-LAG-3 antibody molecule isadministered (e.g., intravenously) at a dose from about 3 to 800 mg,e.g., about 3, 20, 80, 240, or 800 mg. In certain embodiments, theanti-LAG-3 antibody molecule is administered alone at a dose from about20 to 800 mg, e.g., about 3, 20, 80, 240, or 800 mg. In otherembodiments, the anti-LAG-3 antibody molecule is administered at a dosefrom about 3 to 240 mg, e.g., about 3, 20, 80, or 240 mg, in combinationwith a second agent or therapeutic modality, e.g., a second agent ortherapeutic modality described herein. In one embodiment, the anti-LAG-3antibody molecule is administered every 2 weeks (e.g., during weeks 1,3, 5, 7) during each 8 week cycle, e.g., up to 96 weeks.

The antibody molecule can be administered by intravenous infusion at arate of more than 20 mg/min, e.g., 20-40 mg/min, and preferably greaterthan or equal to 40 mg/min to reach a dose of about 35 to 440 mg/m²,preferably about 70 to 310 mg/m², and more preferably, about 110 to 130mg/m². In embodiments, the infusion rate of about 110 to 130 mg/m²achieves a level of about 3 mg/kg. In other embodiments, the antibodymolecule is administered by intravenous infusion at a rate of less than10 mg/min, e.g., less than or equal to 5 mg/min to reach a dose of about1 to 100 mg/m², e.g., about 5 to 50 mg/m², about 7 to 25 mg/m², and morepreferably, about 10 mg/m². In some embodiments, the antibody is infusedover a period of about 30 min.

It is to be noted that dosage values may vary with the type and severityof the condition to be alleviated. It is to be further understood thatfor any particular subject, specific dosage regimens should be adjustedover time according to the individual need and the professional judgmentof the person administering or supervising the administration of thecompositions, and that dosage ranges set forth herein are exemplary onlyand are not intended to limit the scope or practice of the claimedcomposition.

The pharmaceutical compositions of the invention may include a“therapeutically effective amount” or a “prophylactically effectiveamount” of an antibody or antibody portion of the invention. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of the modifiedantibody or antibody fragment may vary according to factors such as thedisease state, age, sex, and weight of the individual, and the abilityof the antibody or antibody portion to elicit a desired response in theindividual. A therapeutically effective amount is also one in which anytoxic or detrimental effects of the modified antibody or antibodyfragment is outweighed by the therapeutically beneficial effects. A“therapeutically effective dosage” preferably inhibits a measurableparameter, e.g., tumor growth rate by at least about 20%, morepreferably by at least about 40%, even more preferably by at least about60%, and still more preferably by at least about 80% relative tountreated subjects. The ability of a compound to inhibit a measurableparameter, e.g., cancer, can be evaluated in an animal model systempredictive of efficacy in human tumors. Alternatively, this property ofa composition can be evaluated by examining the ability of the compoundto inhibit, such inhibition in vitro by assays known to the skilledpractitioner

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

Also within the scope of the invention is a kit comprising an antibodymolecule described herein. The kit can include one or more otherelements including: instructions for use; other reagents, e.g., a label,a therapeutic agent, or an agent useful for chelating, or otherwisecoupling, an antibody to a label or therapeutic agent, or aradioprotective composition; devices or other materials for preparingthe antibody for administration; pharmaceutically acceptable carriers;and devices or other materials for administration to a subject.

Uses of Anti-LAG-3 Antibody Molecules

The anti-LAG-3 antibody molecules disclosed herein have in vitro and invivo diagnostic, as well as therapeutic and prophylactic utilities. Forexample, these molecules can be administered to cells in culture, invitro or ex vivo, or to a subject, e.g., a human subject, e.g., in vivo,to enhance immunity. In one embodiment, the anti-LAG-3 antibodymolecules enhance an immune response in a subject, e.g., by blockade ofLAG-3 (e.g., by blockade of LAG-3 binding to an MHC molecule or otherligands).

Accordingly, in one aspect, the invention provides a method of modifyingan immune response in a subject comprising administering to the subjectthe antibody, molecule described herein, such that the immune responsein the subject is modified. In one embodiment, the immune response isenhanced, stimulated or up-regulated. In some embodiments, theanti-LAG-3 antibody molecule restores, enhances or stimulates anantigen-specific T cell response, e.g., interleukin-2 (IL-2) orinterferon-gamma (IFN-γ), production in an antigen-specific T cellresponse, in the subject. In some embodiments, the immune response is ananti-tumor response. The methods and compositions described herein aresuitable for treating human patients having a disorder that can betreated by augmenting the T-cell mediated immune response. For example,the anti-LAG-3 antibody molecules, alone or in combination, can beadministered to a subject to treat, prevent, and/or diagnose a varietyof disorders, such as cancers (melanoma or hepatic cancers), or aninfectious disorder.

As used herein, the term “subject” is intended to include human andnon-human animals. In one embodiment, the subject is a human subject,e.g., a human patient having a disorder or condition characterized byabnormal LAG-3 functioning. The term “non-human animals” of theinvention includes mammals and non-mammals, such as non-human primates.In one embodiment, the subject is a human. In one embodiment, thesubject is a human patient in need of enhancement of an immune response.In one embodiment, the subject has, or is at risk of, having a disorderdescribed herein, e.g., a cancer or an infectious disorder as describedherein. In certain embodiments, the subject is, or is at risk of being,immunocompromised. For example, the subject is undergoing or hasundergone a chemotherapeutic treatment and/or radiation therapy.Alternatively, or in combination, the subject is, or is at risk ofbeing, immunocompromised as a result of an infection. For example, themethods and compositions described herein can enhance a number of immuneactivities. In one embodiment, the subject has increased number oractivity of tumour-infiltrating T lymphocytes (TILs). In anotherembodiment, the subject has increased expression or activity ofinterferon-gamma (IFN-γ). In yet another embodiment, the subject hasdecreased PD-L1 expression or activity. Accordingly, in certainembodiments, any (e.g., one, two, three, or all) of TILs, IFN-γ, CD8, orPD-L1, can be used as biomarkers for the anti-LAG-3 immunotherapiesdescribed herein.

Therapeutic Uses Cancer

Blockade of LAG-3 by antibodies can enhance an immune response tocancerous cells in a subject. Similar to CD4, LAG-3 interacts with MHCclass II molecules but, unlike CD4, LAG-3 does not interact with thehuman immunodeficiency virus gp120 protein (Baixeras et al. (1992) J.Exp. Med. 176:327-337). Studies have demonstrated direct and specificbinding of LAG-3 to MHC class II on the cell surface (Huard et al.(1996) Eur. J. Immunol. 26:1180-1186). The LAG-3/MHC class IIinteraction plays a role in down-regulating antigen-dependentstimulation of CD4⁺ and CD8⁺ T lymphocytes. The addition of anti-LAG-3antibodies can result in increased T cell proliferation, higherexpression of activation antigens such as CD25, and higherconcentrations of cytokines such as interferon-gamma and interleukin-4(Huard et al. (1994) Eur. J. Immunol. 24:3216-3221). Theintra-cytoplasmic region of LAG-3 can also interact with LAP, a signaltransduction molecule involved in the downregulation of the CD3/TCRactivation pathway (louzalen et al. (2001) Eur. J. Immunol.31:2885-2891). Further, LAG-3 contributes to the suppressor activity ofCD4+CD25⁺ regulatory T cells (T_(reg)). T_(reg) cells express LAG-3 uponactivation and antibodies to LAG-3 inhibit suppression by inducedT_(reg) cells (Huang, C. et al. (2004) Immunity 21:503-513). LAG-3 canalso negatively regulate T cell homeostasis by regulatory T cells inboth T cell-dependent and independent mechanisms (Workman, C. J. andVignali, D. A. (2005) J. Immunol. 174:688-695). Thus, inhibition ofLAG-3 can result in augmenting an immune response.

Accordingly, in one aspect, a method of treating (e.g., reducing orinhibiting) a cancer or tumor in a subject is provided. The methodcomprises administering to the subject an anti-LAG-3 antibody moleculedescribed herein, e.g., a therapeutically effective amount of ananti-LAG-3 antibody molecule, alone or in combination, e.g., with one ormore agents or procedures. In one embodiment, an anti-LAG-3 antibodymolecule may be used alone to inhibit the growth of cancerous tumors.Alternatively, an anti-LAG-3 antibody may be used in combination withone or more of: a standard of care treatment (e.g., for cancers orinfectious disorders), another antibody, an immunomodulator (e.g., anactivator of a costimulatory molecule or an inhibitor of an inhibitorymolecule); a vaccine, e.g., a therapeutic cancer vaccine; or other formsof cellular immunotherapy, as described below. In certain embodiments,the anti-LAG-3 antibody molecule is administered in combination with amodulator of a costimulatory molecule (e.g., an agonist of acostimulatory molecule) or a modulator of an inhibitory molecule (e.g.,an inhibitor of an immune checkpoint inhibitor), e.g., as describedherein.

In one embodiment, the methods are suitable for the treatment of cancerin vivo. To achieve antigen-specific enhancement of immunity, theanti-LAG-3 antibody molecule can be administered together with anantigen of interest. When antibodies to LAG-3 are administered incombination with one or more agents, the combination can be administeredin either order or simultaneously.

Types of Cancer; Theranostic Methods

In certain embodiments, a method of treating a subject, e.g., reducingor ameliorating, a hyperproliferative condition or disorder (e.g., acancer), e.g., solid tumor, a hematological cancer, soft tissue tumor,or a metastatic lesion, in a subject is provided. The method includesadministering to the subject one or more anti-LAG-3 antibody moleculesdescribed herein, alone or in combination with other agents ortherapeutic modalities.

As used herein, the term “cancer” is meant to include all types ofcancerous growths or oncogenic processes, metastatic tissues ormalignantly transformed cells, tissues, or organs, irrespective ofhistopathologic type or stage of invasiveness. Examples of cancerousdisorders include, but are not limited to, solid tumors, hematologicalcancers, soft tissue tumors, and metastatic lesions. Examples of solidtumors include malignancies, e.g., sarcomas, and carcinomas (includingadenocarcinomas and squamous cell carcinomas), of the various organsystems, such as those affecting liver, lung, breast, lymphoid,gastrointestinal (e.g., colon), genitourinary tract (e.g., renal,urothelial cells), prostate and pharynx. Adenocarcinomas includemalignancies such as most colon cancers, rectal cancer, renal-cellcarcinoma, liver cancer, non-small cell carcinoma of the lung, cancer ofthe small intestine and cancer of the esophagus. Squamous cellcarcinomas include malignancies such as those affecting the lung,esophagus, skin, head and neck region, oral cavity, anus, and cervix.Metastatic lesions of the aforementioned cancers can also be treated orprevented using the methods and compositions of the invention.

Exemplary cancers whose growth can be inhibited using the antibodiesmolecules disclosed herein include cancers typically responsive toimmunotherapy. Non-limiting examples of preferred cancers for treatmentinclude melanoma (e.g., an advanced stage (e.g., stage II-IV) melanomaor an HLA-A2 positive melanoma), pancreatic cancer (e.g., advancedpancreatic cancer), solid tumors, breast cancer (e.g., metastatic breastcarcinoma, a breast cancer that does not express one, two or all ofestrogen receptor, progesterone receptor, or Her2/neu, e.g., a triplenegative breast cancer), and renal cell carcinoma (e.g., advanced (e.g.,stage IV) or metastatic renal cell carcinoma (MRCC)). Additionally,refractory or recurrent malignancies can be treated using the antibodymolecules described herein.

Examples of other cancers that can be treated include, e.g., a solidtumor, e.g., prostate cancer (e.g., hormone refractory prostateadenocarcinoma), colon cancer, lung cancer (e.g., non-small cell lungcancer), bone cancer, skin cancer, cancer of the head or neck (e.g.,HPV+ squamous cell carcinoma), cutaneous or intraocular malignantmelanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of theanal region, stomach cancer, testicular cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Merkel cell cancer, solid tumors of childhood, cancer of thebladder, cancer of the kidney or ureter, carcinoma of the renal pelvis,neoplasm of the central nervous system (CNS), tumor angiogenesis, spinalaxis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma,epidermoid cancer, or squamous cell cancer or a hematologicalmalignancy, e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, chronic or acute leukemias including acutemyeloid leukemia, chronic myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia (e.g., relapsed or refractorychronic lymphocytic leukemia), solid tumors of childhood, lymphocyticlymphoma, multiple myeloma, myelodisplastic syndromes, cancer of thebladder, cancer of the kidney or ureter, carcinoma of the renal pelvis,neoplasm of the central nervous system (CNS), primary CNS lymphoma,tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitaryadenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,T-cell lymphoma, environmentally induced cancers including those inducedby asbestos (e.g., mesothelioma), and combinations of said cancers.Treatment of metastatic cancers, e.g., metastatic cancers that expressMHC class II molecules or LAG-3, can be effected using the antibodymolecules described herein.

While not wishing to be bound by theory, in some embodiments, a patientis more likely to respond to treatment with anti-LAG-3, alone or incombination with anti-PD-1 or PD-L1 antibody molecules (optionally incombination with one or more agents as described herein) if the patienthas a cancer that highly expresses PD-L1, and/or the cancer isinfiltrated by anti-tumor immune cells, e.g., TILs. The anti-tumorimmunce cells may be positive for CD8, PD-L1, and/or IFN-γ; thus levelsof CD8, PD-L1, and/or IFN-γ can serve as a readout for levels of TILs inthe microenvironment. In certain embodiments, the cancermicroenvironment is referred to as triple-positive for PD-L1/CD8/IFN-γ.

Accordingly, in certain aspects, this application provides methods ofdetermining whether a tumor sample is positive for one or more of PD-L1,CD8, and IFN-γ, and if the tumor sample is positive for one or more,e.g., two, or all three, of the markers, then administering to thepatient a therapeutically effective amount of an anti-PD-1 antibodymolecule, optionally in combination with one or more otherimmunnomodulators or anti-cancer agents.

In the following indications, a large fraction of patients aretriple-positive for PD-L1/CD8/IFN-γ: lung cancer (squamous); lung cancer(adenocarcinoma); head and neck cancer; stomach cancer; NSCLC; HNSCC;gastric cancers (e.g., MSIhi and/or EBV+); CRC (e.g., MSIhi);nasopharyngeal cancer (NPC); cervical cancer (e.g., squamous); thyroidcancer e.g., papillary thyroid; melanoma; TN breast cancer; and DLBCL(Diffuse Large B-Cell Lymphoma). In breast cancer generally and in coloncancer generally, a moderate fraction of patients is triple-positive forPD-L1/CD8/IFN-γ. In the following indications, a small fraction ofpatients are triple-positive for PD-L1/CD8/IFN-γ: ER+ breast cancer, andpancreatic cancer. These findings are discussed further in Example 4.Regardless of whether a large or small fraction of patients istriple-positive for these markers, screening the patients for thesemarkers allows one to identify a fraction of patients that has anespecially high likelihood of responding favorably to therapy with aLAG-3 antibody, alone or in combination with a PD-1 antibody (e.g., ablocking PD-1 antibody), optionally in combination with one or moreother immunomodulators (e.g., an anti-TIM-3 antibody molecule or ananti-PD-L1 antibody molecule) and/or anti-cancer agents, e.g., thoselisted in Table 7 and disclosed in the publications listed in Table 7.

In some embodiments, the cancer sample is classified as triple-positivefor PDL1/CD8/IFN-γ. This measurement can roughly be broken down into twothresholds: whether an individual cell is classified as positive, andwhether the sample as a whole is classified as positive. First, one canmeasure, within an individual cell, the level of PD-L1, CD8, and/orIFN-γ. In some embodiments, a cell that is positive for one or more ofthese markers is a cell that has a higher level of the marker comparedto a control cell or a reference value. For example, in someembodiments, a high level of PD-L1 in a given cell is a level higherthan the level of PD-L1 in a corresponding non-cancerous tissue in thepatient. As another example, in some embodiments, a high level of CD8 orIFN-γ in a given cell is a level of that protein typically seen in aTIL. Second, one can also measure the percentage of cells in the samplethat are positive for PD-L, CD8, and/or IFN-γ. (It is not necessary fora single cell to express all three markers.) In some embodiments, atriple positive sample is one that has a high percentage of cells, e.g.,higher than a reference value or higher than a control sample, that arepositive for these markers.

In other embodiments, one can measure the levels of PD-L1, CD8, and/orIFN-γ overall in the sample. In this case, a high level of CD8 or IFN-γin the sample can be the level of that protein typically seen in a tumorinfiltrated with TIL. Similarly, a high level of PD-L1 can be the levelof that protein typically seen in a tumor sample, e.g., a tumormicroenvironment.

The identification of subsets of patients that are triple-positive forPD-L1/CD8/IFN-γ, as shown in Example 4 herein, reveals certainsub-populations of patients that are likely to be especially responsiveto PD-1 antibody therapy. For instance, many IM-TN (immunomodulatory,triple negative) breast cancer patients are triple-positive forPDL1/CD8/IFN-γ. IM-TN breast cancer is described in, e.g., Brian D.Lehmann et al., “Identification of human triple-negative breast cancersubtypes and preclinical models for selection of targeted therapies”, JClin Invest. Jul. 1, 2011; 121(7): 2750-2767. Triple-negative breastcancers are those that do not express estrogen receptor (ER),progesterone receptor (PR) and Her2/neu. These cancers are difficult totreat because they are typically not responsive to agents that targetER, PR, and Her2/neu. Triple-negative breast cancers can be furthersubdivided into different classes, one of which is immunomodulatory. Asdescribed in Lehmann et al., IM-TN breast cancer is enriched for factorsinvolved in immune cell processes, for example, one or more of immunecell signaling (e.g., TH1/TH2 pathway, NK cell pathway, B cell receptorsignaling pathway, DC pathway, and T cell receptor signaling), cytokinesignaling (e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway),antigen processing and presentation, signaling through core immunesignal transduction pathways (e.g., NFKB, TNF, and JAK/STAT signaling),genes involved in T-cell function, immune transcription, interferon(IFN) response and antigen processing. Accordingly, in some embodiments,the cancer treated is a cancer that is, or is determined to be, positivefor one or more marker of IM-TN breast cancer, e.g., a factor thatpromotes one or more of immune cell signaling (e.g., TH1/TH2 pathway, NKcell pathway, B cell receptor signaling pathway, DC pathway, and T cellreceptor signaling), cytokine signaling (e.g., cytokine pathway, IL-12pathway, and IL-7 pathway), antigen processing and presentation,signaling through core immune signal transduction pathways (e.g., NFKB,TNF, and JAK/STAT signaling), genes involved in T-cell function, immunetranscription, interferon (IFN) response and antigen processing.

As another example, it is shown herein that a subset of colon cancerpatients having high MSI (microsatellite instability) is alsotriple-positive for PD-L1/CD8/IFN-γ. Accordingly, in some embodiments, aLAG-3 antibody, e.g., a LAG-3 antibody as described herein, alone or incombination with a PD-1 antibody, (optionally in combination with one ormore immunomodulators such as a TIM-3 antibody or a PD-L1 antibody, andone or more anti-cancer agents, e.g., an anti-cancer agent described inTable 7 or in a publication in Table 7) is administered to a patient whohas, or who is identified as having, colon cancer with high MSI, therebytreating the cancer. In some embodiments, a cell with high MSI is a cellhaving MSI at a level higher than a reference value or a control cell,e.g., a non-cancerous cell of the same tissue type as the cancer.

As another example, it is shown herein that a subset of gastric cancerpatients having high MSI, and/or which is EBV+, is also triple-positivefor PD-L1/CD8/IFN-γ. Accordingly, in some embodiments, a LAG-3 antibody,e.g., a LAG-3 antibody as described herein, alone or in combination witha PD-1 antibody, (optionally in combination with one or moreimmunomodulators such as a TIM-3 antibody or a PD-L1 antibody, and oneor more anti-cancer agents, e.g., an anti-cancer agent described inTable 7 or in a publication in Table 7) is administered to a patient whohas, or who is identified as having, gastric cancer with high MSI and/orEBV+, thereby treating the cancer. In some embodiments, a cell with highMSI is a cell having MSI at a level higher than a reference value or acontrol cell, e.g., a non-cancerous cell of the same tissue type as thecancer.

Additionally disclosed herein are methods of assaying a cancer forPD-L1, and then treating the cancer with a LAG-3 antibody, alone or incombination with a PD-1 antibody. As described in Example 5 herein, acancer sample can be assayed for PD-L1 protein levels or mRNA levels. Asample having levels of PD-L1 (protein or mRNA) higher than a referencevalue or a control cell (e.g., a non-cancerous cell) can be classifiedas PD-L1 positive. Accordingly, in some embodiments, a LAG-3 antibody,e.g., a LAG-3 antibody as described herein, alone or in combination witha PD-1 antibody, (optionally in combination with one or more anti-canceragents) is administered to a patient who has, or who is identified ashaving, a cancer that is PD-L1 positive. The cancer may be, e.g.,non-small cell lung (NSCLC) adenocarcinoma (ACA), NSCLC squamous cellcarcinoma (SCC), or hepatocellular carcinoma (HCC).

In some embodiments, the methods herein involve using a LAG-3 antibody,e.g., a LAG-3 antibody as described herein, e.g., in combination with aPD-1 antibody, for treating a cancer that is (or is identified as being)positive for PD-L1. In some embodiments, the cancer is colorectal cancer(e.g., MSI-high), gastric cancer (e.g., MSI-high and/or EBV+), NPC,cervical cancer, breast cancer (e.g., TN breast cancer), and ovariancancer. In some embodiments, the cancer is NSCLC, melanoma, or HNSCC. Insome embodiments, the LAG-3 antibody is administered at a dose of, e.g.,1, 3, 10, or 20 mg/kg.

Based on, e.g, Example 4 herein, it was found that certain gastriccancers that are triple-positive for PDL1/CD8/IFN-γ are also positivefor PIK3CA. Accordingly, in some embodiments, a cancer can be treatedwith a LAG-3 antibody, alone or in combination with an anti-PD1 antibodymolecule (optionally in combination with one or more immunomodulators,e.g., an anti-TIM-3 antibody molecule or an anti-PD-L1 antibodymolecule) and an agent that inhibits PIK3CA. Exemplary agents in thiscategory are described in Stein R C (September 2001). “Prospects forphosphoinositide 3-kinase inhibition as a cancer treatment”.Endocrine-related Cancer 8 (3): 237-48 and Marone R, Cmiljanovic V,Giese B, Wymann M P (January 2008). “Targeting phosphoinositide3-kinase: moving towards therapy”. Biochimica et Biophysica Acta 1784(1): 159-85.

Based on, e.g, Example 4 herein, CRC, e.g., a patient that has (or isidentified as having) MSI-high CRC may be treated with a LAG-3 antibody,alone or in combination with a PD-1 antibody, optionally in combinationwith a therapeutic that targets one or both of RNF43 and BRAF. Forinstance, these cancers may be treated with a LAG-3 antibody and a PD-1antibody, optionally in combination with one or more therapeutics thattarget one or more of RNF43 and BRAF. In embodiments, the one or moretherapeutics include an anti-cancer agent described in Table 7 or apublication listed in Table 7. PD-1 inhibitors, e.g., antibodies, aredescribed herein. RNF43 can be inhibited, e.g., with an antibody, smallmolecule (e.g.,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28)), siRNA, or a Rspo ligand or derivative thereof. BRAFinhibitors (e.g., vemurafenib or dabrafenib) are described herein.

Based on, e.g, Example 4 herein, a patient that has (or is identified ashaving) a squamous cell lung cancer may be treated with a LAG-3 antibodymolecule in combination with a therapeutic that targets PD-1, e.g., aPD-1 antibody molecule, and optionally with one or more anti-canceragents, e.g., an anti-cancer agent described in Table 7 or in apublication in Table 7, or a therapeutic that targets TIM-3, e.g., aTIM-3 antibody.

Based on, e.g, Example 4 herein, a patient that has (or is identified ashaving) a thyroid cancer may be treated with a LAG-3 antibody molecule,alone or in combination with a PD-1 antibody molecule, optionally incombination with a therapeutic that targets BRAF, and optionally incombination with one or more immunomodulators, e.g., an anti-TIM-3antibody molecule, and an anti-PD-L1 antibody molecule. BRAF inhibitors(e.g., vemurafenib or dabrafenib) are described herein, e.g., in Table 7and the publications listed in Table 7.

In some embodiments, the therapies here can be used to treat a patientthat has (or is identified as having) a cancer associated with aninfection, e.g., a viral or bacterial infection. Exemplary cancersinclude cervical cancer, anal cancer, HPV-associated head and necksquamous cell cancer, HPV-associated esophageal papillomas,HHV6-associated lymphomas, EBV-associated lymphomas (including Burkittlymphoma), Gastric MALT lymphoma, other infection-associated MALTlymphomas, HCC, Kaposi's sarcoma. In other embodiments, the cancer is ahematological cancer including but is not limited to a leukemia or alymphoma. For example, the anti-LAG-3 antibody molecule can be used totreat cancers and malignancies including, but not limited to, e.g.,acute leukemias including but not limited to, e.g., B-cell acutelymphoid leukemia (“BALL”), T-cell acute lymphoid leukemia (“TALL”),acute lymphoid leukemia (ALL); one or more chronic leukemias includingbut not limited to, e.g., chronic myelogenous leukemia (CML), chroniclymphocytic leukemia (CLL); additional hematologic cancers orhematologic conditions including, but not limited to, e.g., B cellprolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm,Burkitt's lymphoma, diffuse large B cell lymphoma, Follicular lymphoma,Hairy cell leukemia, small cell- or a large cell-follicular lymphoma,malignant lymphoproliferative conditions, MALT lymphoma, mantle celllymphoma, Marginal zone lymphoma, multiple myeloma, myelodysplasia andmyelodysplastic syndrome, non-Hodgkin's lymphoma, plasmablasticlymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrommacroglobulinemia, and “preleukemia” which are a diverse collection ofhematological conditions united by ineffective production (or dysplasia)of myeloid blood cells, and the like.

In one embodiment, the cancer is a melanoma, e.g., an advanced melanoma.In one embodiment, the cancer is an advanced or unresectable melanomathat does not respond to other therapies. In other embodiments, thecancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation).In yet other embodiments, the anti-LAG-3 antibody molecule isadministered after treatment with an anti-CTLA4 antibody (e.g.,ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib ordabrafenib).

Methods and compositions disclosed herein are useful for treatingmetastatic lesions associated with the aforementioned cancers.

Combination of Anti-LAG-3 Antibodies with Cancer Vaccines

Antibody molecules to LAG-3 can be combined with an immunogenic agent,such as cancerous cells, purified tumor antigens (including recombinantproteins, peptides (e.g., HLA-A2 peptides), and carbohydrate molecules),cells, and cells transfected with genes encoding immune stimulatingcytokines (He et al. (2004) J. Immunol. 173:4919-28). Non-limitingexamples of tumor vaccines that can be used include, e.g., peptides ofmelanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2,MART1 and/or tyrosinase, or tumor cells transfected to express thecytokine GM-CSF, DNA-based vaccines, RNA-based vaccines, and virallytransduced-based vaccines. The cancer vaccine may be prophylactic ortherapeutic.

LAG-3 blockade can be combined with a vaccination protocol. Manyexperimental strategies for vaccination against tumors have been devised(see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCOEducational Book Spring: 60-62; Logothetis, C., 2000, ASCO EducationalBook Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring:414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see alsoRestifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 inDeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice ofOncology. Fifth Edition). In one of these strategies, a vaccine isprepared using autologous or allogeneic tumor cells. These cellularvaccines have been shown to be most effective when the tumor cells aretransduced to express GM-CSF. GM-CSF has been shown to be a potentactivator of antigen presentation for tumor vaccination (Dranoff et al.(1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).

LAG-3 blockade can be used in conjunction with a collection ofrecombinant proteins and/or peptides expressed in a tumor in order togenerate an immune response to these proteins. These proteins arenormally viewed by the immune system as self antigens and are thereforetolerant to them. The tumor antigen may also include the proteintelomerase, which is required for the synthesis of telomeres ofchromosomes and which is expressed in more than 85% of human cancers andin only a limited number of somatic tissues (Kim, N. et al. (1994)Science 266: 2011-2013). (These somatic tissues may be protected fromimmune attack by various means). Tumor antigen may also be“neo-antigens” expressed in cancer cells because of somatic mutationsthat alter protein sequence or create fusion proteins between twounrelated sequences (e.g., bcr-abl in the Philadelphia chromosome), oridiotype from B cell tumors.

Other tumor vaccines may include the proteins from viruses implicated inhuman cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses(HBV and HCV), Epstein-Barr virus (EBV), and Kaposi's Herpes SarcomaVirus (KHSV). Another form of tumor specific antigen which may be usedin conjunction with LAG-3 blockade is purified heat shock proteins (HSP)isolated from the tumor tissue itself. These heat shock proteins containfragments of proteins from the tumor cells and these HSPs are highlyefficient at delivery to antigen presenting cells for eliciting tumorimmunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura,Y. et al. (1997) Science 278:117-120).

Dendritic cells (DC) are potent antigen presenting cells that can beused to prime antigen-specific responses. DC's can be produced ex vivoand loaded with various protein and peptide antigens as well as tumorcell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCsmay also be transduced by genetic means to express these tumor antigensas well. DCs have also been fused directly to tumor cells for thepurposes of immunization (Kugler, A. et al. (2000) Nature Medicine6:332-336). As a method of vaccination, DC immunization may beeffectively combined with LAG-3 blockade to activate more potentanti-tumor responses.

In some embodiments, the combination further includes an inhibitor oractivator of an immune checkpoint modulator (e.g., a PD-1 inhibitor(e.g., an anti-PD-1 antibody molecule), a PD-L1 inhibitor (e.g., ananti-PD-L1 antibody molecule), a TIM-3 modulator (e.g., a TIM-3activator or inhibitor, e.g., an anti-TIM-3 antibody molecule), or aCTLA-4 inhibitor (e.g., an anti-CTLA4 antibody), or any combinationthereof.

LAG-3 blockade may also be combined with a standard cancer treatment.LAG-3 blockade may be effectively combined with chemotherapeuticregimes. In these instances, it may be possible to reduce the dose ofchemotherapeutic reagent administered (Mokyr, M. et al. (1998) CancerResearch 58: 5301-5304). In certain embodiments, the methods andcompositions described herein are administered in combination with oneor more of other antibody molecules, chemotherapy, other anti-cancertherapy (e.g., targeted anti-cancer therapies, or oncolytic drugs),cytotoxic agents, immune-based therapies (e.g., cytokines), surgicaland/or radiation procedures. Exemplary cytotoxic agents that can beadministered in combination with include antimicrotubule agents,topoisomerase inhibitors, anti-metabolites, mitotic inhibitors,alkylating agents, anthracyclines, vinca alkaloids, intercalatingagents, agents capable of interfering with a signal transductionpathway, agents that promote apoptosis, proteosome inhibitors, andradiation (e.g., local or whole body irradiation).

Alternatively, or in combination with the aforesaid combinations, themethods and compositions described herein can be administered incombination with one or more of: an immunomodulator (e.g., an activatorof a costimulatory molecule or an inhibitor of an inhibitory molecule);a vaccine, e.g., a therapeutic cancer vaccine; or other forms ofcellular immunotherapy.

Exemplary non-limiting combinations and uses of the anti-LAG-3 antibodymolecules include the following.

In certain embodiments, the anti-LAG-3 antibody molecule is administeredin combination with a modulator of a costimulatory molecule or aninhibitory molecule, e.g., a co-inhibitory ligand or receptor.

In one embodiment, the anti-LAG-3 antibody molecule is administered incombination with a modulator, e.g., agonist, of a costimulatorymolecule. In one embodiment, the agonist of the costimulatory moleculeis chosen from an agonist (e.g., an agonistic antibody or solublefusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS(CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT,NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand.

In another embodiment, the anti-LAG-3 antibody molecule is used incombination with a costimulatory molecule, e.g., an agonist associatedwith a positive signal that includes a costimulatory domain of CD28,CD27, ICOS and GITR.

Exemplary GITR agonists include, e.g., GITR fusion proteins andanti-GITR antibodies (e.g., bivalent anti-GITR antibodies) such as,e.g., a GITR fusion protein described in U.S. Pat. No. 6,111,090,European Patent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT PublicationNos.: WO 2010/003118 and 2011/090754, or an anti-GITR antibodydescribed, e.g., in U.S. Pat. No. 7,025,962, European Patent No.:1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat.No. 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO2011/028683, PCT Publication No.: WO 2013/039954, PCT Publication No.:WO2005/007190, PCT Publication No.: WO 2007/133822, PCT Publication No.:WO2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO2001/03720, PCT Publication No.: WO99/20758, PCT Publication No.:WO2006/083289, PCT Publication No.: WO 2005/115451, U.S. Pat. No.7,618,632, and PCT Publication No.: WO 2011/051726. One exemplaryanti-GITR antibody is TRX518.

In one embodiment, the anti-LAG-3 antibody molecule is administered incombination with an inhibitor of an inhibitory molecule (e.g., aninhibitor of an immune checkpoint molecule). It will be understood bythose of ordinary skill in the art, that the term “immune checkpoints”means a group of molecules on the cell surface of CD4 and CD8 T cells.These molecules can effectively serve as “brakes” to down-modulate orinhibit an anti-tumor immune response. Immune checkpoint moleculesinclude, but are not limited to, Programmed Death 1 (PD-1), CytotoxicT-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, andTIM-3, which directly inhibit immune cells, immunotherapeutic agentswhich can act as immune checkpoint inhibitors useful in the methods ofthe present invention, include, but are not limited to, inhibitors ofPD-1, PD-L1, PD-L2, CTLA-4, TIM-3, VISTA, BTLA, TIGIT, LAIR1, CD160,2B4, CEACAM (e.g., CEACAM-1 and/or CEACAM-5), and/or TGFR beta.Inhibition of an inhibitory molecule can be performed by inhibition atthe DNA, RNA or protein level. In embodiments, an inhibitory nucleicacid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expressionof an inhibitory molecule. In other embodiments, the inhibitor of aninhibitory signal is, a polypeptide e.g., a soluble ligand, or anantibody or antibody fragment, that binds to the inhibitory molecule.Exemplary TIM-3 antibody molecules include, but are not limited to,MBG220, MBG227, and MBG219. Exemplary TIGIT inhibitors include, but arenot limited to, 10A7 and 1F4 (Roche).

Further examples of modulators include but are not limited to B7-H5,ENTPD1, ENTPD2, SIGGIR, B7-1, B7-2, VSIG4, TIM-1, CD200, RANKL, andP2X7.

In one embodiment, the inhibitor is a soluble ligand (e.g., a CTLA-4-Igor a TIM-3-Ig), or an antibody or antibody fragment that binds to PD-L1,PD-L2 or CTLA4. For example, the anti-LAG-3 antibody molecule can beadministered in combination with an anti-CTLA-4 antibody, e.g.,ipilimumab. Exemplary anti-CTLA4 antibodies include Tremelimumab (IgG2monoclonal antibody available from Pfizer, formerly known asticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known asMDX-010, CAS No. 477202-00-9). In one embodiment, the anti-LAG-3antibody molecule is administered after treatment, e.g., after treatmentof a melanoma, with an anti-CTLA4 antibody (e.g., ipilimumab) with orwithout a BRAF inhibitor (e.g., vemurafenib or dabrafenib). In oneembodiment, the anti-CTLA-4 antibody, e.g., ipilimumab, is administeredat a dose of about 3 mg/kg. The anti-LAG-3 antibody molecule can beadministered in combination at a dose from about 20 to 800 mg, e.g.,about 20, 80, 240, or 800 mg. In one embodiment, the anti-LAG-3 antibodymolecule is administered every 2 weeks (e.g., during weeks 1, 3, 5, 7)during each 8 week cycle, e.g., up to 96 weeks.

In another embodiment, the anti-LAG-3 antibody molecule is administeredin combination with an anti-PD-1 antibody molecule. Exemplary doses thatcan be use include a dose of anti-PD-1 antibody molecule of about 1 to10 mg/kg, e.g., 3 mg/kg. The anti-LAG-3 antibody molecule can beadministered in combination at a dose from about 20 to 800 mg, e.g.,about 20, 80, 240, or 800 mg. In one embodiment, the anti-LAG-3 antibodymolecule is administered every 2 weeks (e.g., during weeks 1, 3, 5, 7)during each 8 week cycle, e.g., up to 96 weeks.

Immune inhibitory molecules, e.g., PD-1 and LAG-3, can regulate, e.g.,synergistically, T-cell function to promote tumoral immune escape. Inanother embodiment, the anti-LAG-3 antibody molecule is administered incombination with an anti-TIM-3 antibody molecule. In still anotherembodiment, the anti-LAG-3 antibody molecule is administered incombination with an anti-PD-L1 antibody molecule. In yet otherembodiments, the anti-LAG-3 antibody molecule is administered incombination with an anti-PD-1 antibody and an anti-TIM-3 antibody. Incertain embodiments, the anti-LAG-3 antibody molecule is administered incombination with an anti-PD-1 antibody and an anti-PD-L1 antibody. Incertain embodiments, the anti-LAG-3 antibody molecule is administered incombination with an anti-TIM-3 antibody and an anti-PD-L1 antibody. Thecombination of antibodies recited herein can be administered separately,e.g., as separate antibodies, or linked, e.g., as a bispecific ortrispecific antibody molecule. In another embodiment, the anti-LAG-3antibody molecule is administered in combination with a CEACAM inhibitor(e.g., CEACAM-1 and/or CEACAM-5 inhibitor), e.g., an anti-CEACAMantibody molecule. In another embodiment, the anti-LAG-3 antibodymolecule, is administered in combination with a CEACAM-1 inhibitor,e.g., an anti-CEACAM-1 antibody molecule. In another embodiment, theanti-LAG-3 antibody molecule is administered in combination with aCEACAM-5 inhibitor, e.g., an anti-CEACAM-5 antibody molecule. In oneembodiment, a bispecific antibody that includes an anti-LAG-3 antibodymolecule and an anti-PD-1 or anti-LAG-3 antibody is administered. Incertain embodiments, the combination of antibodies recited herein isused to treat a cancer, e.g., a cancer as described herein (e.g., asolid tumor). The efficacy of the aforesaid combinations can be testedin animal models known in the art. For example, the animal models totest the synergistic effect of anti-LAG-3 and anti-PD-1 are described,e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27). In one embodiment,the inhibitor of CEACAM (e.g., CEACAM-1 and/or CEACAM-5) is ananti-CEACAM antibody molecule. Without wishing to be bound by theory,CEACAM-1 has been described as a ligand and partner of TIM-3 (see e.g.,WO 2014/022332). Synergistic in vivo effect of the combination ofanti-TIM-3 and anti-CEACAM-1 antibodies have been detected in xenograftcancer models (see e.g., WO 2014/022332). Tumors are believed to useCEACAM-1 or CEACAM-5 to inhibit the immune system, as described in,e.g., Markel et al. J Immunol. 2002 Mar. 15; 168(6):2803-10; Markel etal. J Immunol. 2006 Nov. 1; 177(9):6062-71; Markel et al. Immunology.2009 February; 126(2):186-200; Markel et al. Cancer Immunol Immunother.2010 February; 59(2):215-30; Ortenberg et al. Mol Cancer Ther. 2012June; 11(6):1300-10; Stern et al. J Immunol. 2005 Jun. 1;174(11):6692-701; Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii: e12529.Thus, CEACAM inhibitors can be used with the other immunomodulatorsdescribed herein (e.g., anti-LAG-3, anti-PD-1, or anti-TIM-3 inhibitors)to enhance an immune response against a cancer, e.g., melanoma, lungcancer (e.g., NSCLC), bladder, colon or ovarian cancer, or other cancersas described herein. In one embodiment, the inhibitor of CEACAM is ananti-CEACAM-1 antibody as described in WO 2010/125571, WO 2013/82366 andWO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4 or arecombinant form thereof, as described in, e.g., US 2004/0047858, U.S.Pat. No. 7,132,255 and WO 99/52552. In other embodiments, theanti-CEACAM antibody is an anti-CEACAM-1 and/or anti-CEACAM-5 antibodymolecule as described in, e.g., WO 2010/125571, WO 2013/054331 and US2014/0271618.

In some embodiments, the LAG-3 and PD-1 immune inhibitory molecules(e.g., antibody molecules) are administered in combination with eachother, e.g., to treat cancer. In some embodiments, the patient is apatient who progressed (e.g., experienced tumor growth) during therapywith a PD-1 inhibitor (e.g., an antibody molecule as described herein)and/or a PD-L1 inhibitor (e.g., antibody molecule). In some embodiments,therapy with the PD-1 antibody molecule and/or PDL1 antibody molecule iscontinued, and a LAG-3 immune inhibitory molecule (e.g., antibody) isadded to the therapy. In other embodiments, the anti-LAG-3 antibodymolecule is administered in combination with a cytokine, e.g.,interleukin-21, interleukin-2, or interleukin 15. In certainembodiments, the combination of anti-LAG-3 antibody molecule andcytokine described herein is used to treat a cancer, e.g., a cancer asdescribed herein (e.g., a solid tumor or melanoma).

Exemplary immunomodulators that can be used in combination with theanti-LAG-3 antibody molecules include, but are not limited to, e.g.,afutuzumab (available from Roche®); pegfilgrastim (Neulasta®);lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid(CC4047); and cytokines, e.g., IL-21 or IRX-2 (mixture of humancytokines including interleukin 1, interleukin 2, and interferon γ, CAS951209-71-5, available from IRX Therapeutics).

Another example of such a combination is an anti-LAG-3 antibody incombination with decarbazine for the treatment of melanoma. Anotherexample of such a combination is an anti-LAG-3 antibody molecule incombination with interleukin-2 (IL-2) for the treatment of melanoma. Inone embodiment the anti-LAG-3 antibody molecule can be combined withIL-21. Without being bound by theory, the combined use of LAG-3 blockadeand chemotherapy is that cell death, is believed to be facilitated bycell death, that is a consequence of the cytotoxic action of mostchemotherapeutic compounds, which can result in increased levels oftumor antigen in the antigen presentation pathway. Other combinationtherapies that may result in synergy with LAG-3 blockade through celldeath are radiation, surgery, and hormone deprivation. Each of theseprotocols creates a source of tumor antigen in the host. Angiogenesisinhibitors may also be combined with LAG-3 blockade. Inhibition ofangiogenesis leads to tumor cell death which may feed tumor antigen intohost antigen presentation pathways.

LAG-3 blocking antibodies can also be used in combination withbispecific antibodies. Bispecific antibodies can be used to target twoseparate antigens. For example anti-Fc receptor/anti tumor antigen(e.g., Her-2/neu) bispecific antibodies have been used to targetmacrophages to sites of tumor. This targeting may more effectivelyactivate tumor specific responses. The T cell arm of these responseswould by augmented by the use of LAG-3 blockade. Alternatively, antigenmay be delivered directly to DCs by the use of bispecific antibodieswhich bind to tumor antigen and a dendritic cell specific cell surfacemarker.

Tumors evade host immune surveillance by a large variety of mechanisms.Many of these mechanisms may be overcome by the inactivation of proteinswhich are expressed by the tumors and which are immunosuppressive. Theseinclude among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163:1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13:198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274:1363-1365). Antibodies to each of these entities may be used incombination with anti-LAG-3 to counteract the effects of theimmunosuppressive agent and favor tumor immune responses by the host.

Other antibodies which may be used to activate host immuneresponsiveness can be used in combination with anti-LAG-3. These includemolecules on the surface of dendritic cells which activate DC functionand antigen presentation. Anti-CD40 antibodies are able to substituteeffectively for T cell helper activity (Ridge, J. et al. (1998) Nature393: 474-478) and can be used in conjunction with LAG-3 antibodies (Ito,N. et al. (2000) Immunobiology 201 (5) 527-40). Activating antibodies toT cell costimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No.5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169),4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), andICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) may also providefor increased levels of T cell activation.

Additional exemplary treatments that can be used in combination with theanti-LAG-3 antibody molecules are described in the section entitled“Combination Therapies” below.

In all of the above methods, LAG-3 blockade can be combined with otherforms of immunotherapy such as cytokine treatment (e.g., interferons,GM-CSF, G-CSF, IL-2, IL-21), or bispecific antibody therapy, whichprovides for enhanced presentation of tumor antigens (see, e.g.,Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994)Structure 2:1121-1123).

Methods of administering the anti-LAG-3 antibody molecules are known inthe art and are described below. Suitable dosages of the molecules usedwill depend on the age and weight of the subject and the particular drugused. Dosages and therapeutic regimens of the anti-LAG-3 antibodymolecule can be determined by a skilled artisan. In certain embodiments,the anti-LAG-3 antibody molecule is administered by injection (e.g.,subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g.,about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about3 mg/kg, or about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, or about 40mg/kg. In some embodiments, the anti-LAG-3 antibody molecule isadministered at a dose of about 1-3 mg/kg, or about 3-10 mg/kg. In someembodiments, the anti-LAG-3 antibody molecule is administered at a doseof about 0.5-2, 2-4, 2-5, 5-15, or 5-20 mg/kg. The dosing schedule canvary from e.g., once a week to once every 2, 3, or 4 weeks. In oneembodiment, the anti-LAG-3 antibody molecule is administered at a dosefrom about 10 to 20 mg/kg every other week.

The antibody molecule can be used in unconjugated forms or conjugated toa second agent, e.g., a cytotoxic drug, radioisotope, or a protein,e.g., a protein toxin or a viral protein. This method includes:administering the antibody molecule, alone or conjugated to a cytotoxicdrug, to a subject requiring such treatment. The antibody molecule canbe used to deliver a variety of therapeutic agents, e.g., a cytotoxicmoiety, e.g., a therapeutic drug, a radioisotope, molecules of plant,fungal, or bacterial origin, or biological proteins (e.g., proteintoxins) or particles (e.g., a recombinant viral particles, e.g.; via aviral coat protein), or mixtures thereof.

Additional Combination Therapy

The anti-LAG-3 antibody molecule can be used in combination with othertherapies. For example, the combination therapy can include acomposition of the present invention co-formulated with, and/orco-administered with, one or more additional therapeutic agents, e.g.,one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonetreatment, vaccines, and/or other immunotherapies. In other embodiments,the antibody molecules are administered in combination with othertherapeutic treatment modalities, including surgery, radiation,cryosurgery, and/or thermotherapy. Such combination therapies mayadvantageously utilize lower dosages of the administered therapeuticagents, thus avoiding possible toxicities or complications associatedwith the various monotherapies. In one embodiment, the anti-LAG-3antibody is administered in combination with the therapies disclosedherein at a dose from about 20 to 800 mg, e.g., about 20, 80, 240, or800 mg. In one embodiment, the anti-LAG-3 antibody molecule isadministered weekly, every 2 weeks (e.g., during weeks 1, 3, 5, 7)during each 8 week cycle, e.g., up to 96 weeks.

In one embodiment, the compositions described herein are administered incombination with other antibody molecules, e.g., one or more of: anantibody described herein, a chemotherapeutic agent, a cytotoxic agent,surgical and/or radiation procedures. Exemplary chemotherapeutic and/orcytotoxic agents that can be administered in combination with includeantimicrotubule agents, topoisomerase inhibitors, antimetabolites,mitotic inhibitors, alkylating agents, intercalating agents, agentscapable of interfering with a signal transduction pathway, agents thatpromote apoptosis and radiation. Exemplary other antibody molecules thatcan be administered in combination include, but are not limited to,checkpoint inhibitors (e.g., PD-1, PD-L); antibodies that stimulate animmune cell (e.g., agonistic GITR or CD137 antibodies); anti-cancerantibodies (e.g., rituximab (Rituxan® or MabThera®), trastuzumab(Herceptin®), cetuximab (Erbitux®), among others.

By “in combination with,” it is not intended to imply that the therapyor the therapeutic agents must be administered at the same time and/orformulated for delivery together, although these methods of delivery arewithin the scope described herein. The anti-LAG-3 antibody molecules canbe administered concurrently with, prior to, or subsequent to, one ormore other additional therapies or therapeutic agents. The anti-LAG-3antibody molecule and the other agent or therapeutic protocol can beadministered in any order. In general, each agent will be administeredat a dose and/or on a time schedule determined for that agent. In willfurther be appreciated that the additional therapeutic agent utilized inthis combination may be administered together in a single composition oradministered separately in different compositions. In general, it isexpected that additional therapeutic agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually. The effectof the two treatments can be partially additive, wholly additive, orgreater than additive. The delivery can be such that an effect of thefirst treatment delivered is still detectable when the second isdelivered.

Antibody molecules can be administered in combination with one or moreof the existing modalities for treating cancers, including, but notlimited to: surgery; radiation therapy (e.g., external-beam therapywhich involves three dimensional, conformal radiation therapy where thefield of radiation is designed.

In certain embodiments, the anti-LAG-3 molecules described herein areadministered in combination with one or more inhibitors of PD-1, PD-L1and/or PD-L2 known in the art. The antagonist may be an antibody, anantigen binding fragment thereof, an immunoadhesin, a fusion protein, oroligopeptide.

In some embodiments, the other anti-PD-1 antibody is chosen fromMDX-1106, Merck 3475 or CT-011.

In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., animmunoadhesin comprising an extracellular or PD-1 binding portion ofPD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of animmunoglobulin sequence).

In some embodiments, the PD-L1 inhibitor is anti-PD-L1 antibody. In someembodiments, the anti-PD-L1 binding antagonist is chosen fromYW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105,also known as BMS-936559, is an anti-PD-L1 antibody described inWO2007/005874. Antibody YW243.55.S70 (heavy and light chain variableregion sequences shown in SEQ ID Nos. 20 and 21, respectively) is ananti-PD-L1 described in WO 2010/077634.

In some embodiments, the anti-PD-1 antibody is Nivolumab. Alternativenames for Nivolumab include MDX-1106, MDX-1106-04, ONO-4538, orBMS-936558. In some embodiments, the anti-PD-1 antibody is Nivolumab(CAS Registry Number: 946414-94-4). Nivolumab (also referred to asBMS-936558 or MDX1106; Bristol-Myers Squibb) is a fully human IgG4monoclonal antibody which specifically blocks PD-1. Nivolumab (clone5C4) and other human monoclonal antibodies that specifically bind toPD-1 are disclosed in U.S. Pat. No. 8,008,449, EP2161336 andWO2006/121168.

Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibodythat binds to PD-1. Pidilizumab and other humanized anti-PD-1 monoclonalantibodies are disclosed in WO2009/101611.

In other embodiments, the anti-PD-1 antibody is pembrolizumab.Pembrolizumab (Trade name Keytruda formerly lambrolizumab also known asMK-3475) disclosed, e.g., in Hamid, O. et al. (2013) New England Journalof Medicine 369 (2): 134-44.

Other anti-PD-1 antibodies include AMP 514 (Amplimmune), LZV178, andLZV181, among others, e.g., anti-PD1 antibodies disclosed in U.S. Pat.No. 8,609,089, US 2010028330, and/or US 20120114649.

In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C(also referred to as A09-246-2; Merck Serono) is a monoclonal antibodythat binds to PD-L1. Pembrolizumab and other humanized anti-PD-L1antibodies are disclosed in WO2013/079174.

MDPL3280A (Genentech/Roche) is a human Fc optimized IgG1 monoclonalantibody that binds to PD-L. MDPL3280A and other human monoclonalantibodies to PD-L1 are disclosed in U.S. Pat. No. 7,943,743 and U.S.Publication No.: 20120039906. Other anti-PD-L1 binding agents includeYW243.55.S70 (heavy and light chain variable regions are shown in SEQ IDNOs 20 and 21 in WO2010/077634) and MDX-1105 (also referred to asBMS-936559, and, e.g., anti-PD-L1 binding agents disclosed inWO2007/005874).

In some embodiments, the PD-1 inhibitor is AMP-224. AMP-224 (B7-DCIg;Amplimmune; e.g., disclosed in WO2010/027827 and WO2011/066342), is aPD-L2 Fc fusion soluble receptor that blocks the interaction between PD1and B7-H1.

In some embodiments, the PD-1 inhibitor is MEDI4736.

Cancer Therapies

Exemplary combinations of anti-LAG-3 antibody molecules (alone or incombination with other stimulatory agents) and standard of care forcancer, include at least the following. In certain embodiments, theanti-LAG-3 antibody molecule, e.g., the anti-LAG-3 antibody moleculedescribed herein, is used in combination with a standard of cancer carechemotherapeutic agent including, but not limited to, anastrozole(Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®),busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine(Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin(Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin(Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® orNeosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabineliposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin,polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate(Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine(Tirazone®), topotecan hydrochloride for injection (Hycamptin®),vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®),ibrutinib, idelalisib, and brentuximab vedotin.

Exemplary alkylating agents include, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®,Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracilnitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®,Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®,Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide(Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman(Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®),triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa(Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®),lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine(DTIC-Dome®). Additional exemplary alkylating agents include, withoutlimitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® andTemodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard,Alkeran®); Altretamine (also known as hexamethylmelamine (HMM),Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan(Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (alsoknown as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® andPlatinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® andNeosar®); Dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine(HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine(Matulane®); Mechlorethamine (also known as nitrogen mustard, mustineand mechloroethamine hydrochloride, Mustargen®); Streptozocin(Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA,Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®,Revimmune®); and Bendamustine HCl (Treanda®).

Exemplary anthracyclines include, e.g., doxorubicin (Adriamycin® andRubex®); bleomycin (Lenoxane®); daunorubicin (dauorubicin hydrochloride,daunomycin, and rubidomycin hydrochloride, Cerubidine®); daunorubicinliposomal (daunorubicin citrate liposome, DaunoXome®); mitoxantrone(DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®,Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin;ravidomycin; and desacetylravidomycin.

Exemplary vinca alkaloids that can be used in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule) include, but are not limited to, vinorelbine tartrate(Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®));vinblastine (also known as vinblastine sulfate, vincaleukoblastine andVLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®).

Exemplary proteosome inhibitors that can be used in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), include, but are not limited to, bortezomib (Velcade®);carfilzomib (PX-171-007,(S)-4-Methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide);marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib(CEP-18770); andO-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide(ONX-0912).

In some embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a tyrosinekinase inhibitor (e.g., a receptor tyrosine kinase (RTK) inhibitor).Exemplary tyrosine kinase inhibitor include, but are not limited to, anepidermal growth factor (EGF) pathway inhibitor (e.g., an epidermalgrowth factor receptor (EGFR) inhibitor), a vascular endothelial growthfactor (VEGF) pathway inhibitor (e.g., a vascular endothelial growthfactor receptor (VEGFR) inhibitor (e.g., a VEGFR-1 inhibitor, a VEGFR-2inhibitor, a VEGFR-3 inhibitor)), a platelet derived growth factor(PDGF) pathway inhibitor (e.g., a platelet derived growth factorreceptor (PDGFR) inhibitor (e.g., a PDGFR-β inhibitor)), a RAF-1inhibitor, a KIT inhibitor, and a RET inhibitor. In some embodiments,the anti-cancer agent used in combination with the hedgehog inhibitor isselected from the group consisting of: axitinib (AG013736), bosutinib(SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®,BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib(Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®),lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®),semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib(PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK),trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®),cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®),nilotinib (TASIGNA®), sorafenib (NEXAVAR®), alemtuzumab (CAMPATH®),gemtuzumab ozogamicin (MYLOTARG®), ENMD-2076, PCI-32765, AC220,dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228,AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, pelitinib(EKB-569), vandetanib (zactima), WZ3146, WZ4002, WZ8040, ABT-869(linifanib), AEE788, AP24534 (ponatinib), AV-951 (tivozanib), axitinib,BAY 73-4506 (regorafenib), brivanib alaninate (BMS-582664), brivanib(BMS-540215), cediranib (AZD2171), CHIR-258 (dovitinib), CP 673451,CYC116, E7080, Ki8751, masitinib (AB1010), MGCD-265, motesanibdiphosphate (AMG-706), MP-470, OSI-930, Pazopanib Hydrochloride,PD173074, Sorafenib Tosylate (Bay 43-9006), SU 5402, TSU-68 (SU6668),vatalanib, XL880 (GSK1363089, EXEL-2880). Selected tyrosine kinaseinhibitors are chosen from sunitinib, erlotinib, gefitinib, orsorafenib.

In certain embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a VascularEndothelial Growth Factor (VEGF) receptor inhibitors, including but notlimited to, Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanibalaninate (BMS-582664,(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate);Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®);Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®);Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanibdihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate(AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid(TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3);Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4);N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide(BMS38703, CAS 345627-80-7);(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol (BMS690514);N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine(XL647, CAS 781613-23-8);4-Methyl-3-[[1-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide(BHG712, CAS 940310-85-0); and Aflibercept (Eylea®).

Exemplary anti-VEGF antibodies include, but are not limited to, amonoclonal antibody that binds to the same epitope as the monoclonalanti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709; arecombinant humanized anti-VEGF monoclonal antibody generated accordingto Presta et al. (1997) Cancer Res. 57:4593-4599. In one embodiment, theanti-VEGF antibody is Bevacizumab (BV), also known as rhuMAb VEGF orAVASTIN®. It comprises mutated human IgG1 framework regions andantigen-binding complementarity-determining regions from the murineanti-hVEGF monoclonal antibody A.4.6.1 that blocks binding of human VEGFto its receptors. Bevacizumab and other humanized anti-VEGF antibodiesare further described in U.S. Pat. No. 6,884,879 issued Feb. 26, 2005.Additional antibodies include the G6 or B20 series antibodies (e.g.,G6-31, B20-4.1), as described in PCT Publication No. WO2005/012359, PCTPublication No. WO2005/044853, the contents of these patent applicationsare expressly incorporated herein by reference. For additionalantibodies see U.S. Pat. Nos. 7,060,269, 6,582,959, 6,703,020,6,054,297; WO98/45332; WO 96/30046; WO94/10202; EP 0666868B1; U.S.Patent Application Publication Nos. 2006009360, 20050186208,20030206899, 20030190317, 20030203409, and 20050112126; and Popkov etal, Journal of Immunological Methods 288: 149-164 (2004). Otherantibodies include those that bind to a functional epitope on human VEGFcomprising of residues F17, Ml 8, D19, Y21, Y25, Q89, 191, Kl 01, El 03,and C104 or, alternatively, comprising residues F17, Y21, Q22, Y25, D63,183 and Q89.

In some embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a PI3Kinhibitor. In one embodiment, the PI3K inhibitor is an inhibitor ofdelta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can beused in combination are described in, e.g., WO 2010/036380; WO2010/006086, WO 09/114870, WO 05/113556. Exemplary PI3K inhibitors thatcan be used in combination include, e.g., GSK 2126458, GDC-0980,GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL263, SF1126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235).

In some embodiments, the anti-LAG-3 antibody molecule described herein,alone or in combination with another immunomodulator (e.g., ananti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule), is used incombination with a mTOR inhibitor, e.g., one or more mTOR inhibitorschosen from one or more of rapamycin, temsirolimus (TORISEL®), AZD8055,BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615,KU-0063794, WYE-354, Palomid 529 (P529), PF-04691502, or PKI-587.ridaforolimus (formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R, 16E, 18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001);rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3);emsirolimus,(5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol(AZD8055);2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(PF04691502, CAS 1013101-36-4); andN²-[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-,inner salt (SF1126, CAS 936487-67-1), and XL765.

In some embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a BRAFinhibitor, e.g., GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, andsorafenib tosylate (Bay 43-9006).

In some embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a MEKinhibitor. In some embodiments, the combination of the anti-LAG-3antibody and the MEK inhibitor is used to treat a cancer (e.g., a cancerdescribed herein). In some embodiments, the cancer treated with thecombination is chosen from a melanoma, a colorectal cancer, a non-smallcell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer,a pancreatic cancer, a hematological malignancy or a renal cellcarcinoma. In certain embodiments, the cancer includes a BRAF mutation(e.g., a BRAF V600E mutation), a BRAF wildtype, a KRAS wildtype or anactivating KRAS mutation. The cancer may be at an early, intermediate orlate stage. Any MEK inhibitor can be used in combination including, butnot limited to, ARRY-142886, G02442104 (also known as GSK1120212),RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (also known as AZD6244orselumetinib), BIX 02188, BIX 02189, CI-1040 (PD-184352), PD0325901,PD98059, U0126, GDC-0973 (Methanone,[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-(25)-2-piperidinyl-1-azetidinyl]-),G-38963, G02443714 (also known as AS703206), or a pharmaceuticallyacceptable salt or solvate thereof. Additional examples of MEKinhibitors are disclosed in WO 2013/019906, WO 03/077914, WO2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, thecontents of which are incorporated herein by reference.

In another embodiment, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used in combination with one, twoor all of oxaliplatin, leucovorin or 5-FU (e.g., a FOLFOX co-treatment).Alternatively or in combination, the combination further includes a VEGFinhibitor (e.g., a VEGF inhibitor as disclosed herein). In someembodiments, the combination of the anti-LAG-3 antibody, the FOLFOXco-treatment, and the VEGF inhibitor is used to treat a cancer (e.g., acancer described herein). In some embodiments, the cancer treated withthe combination is chosen from a melanoma, a colorectal cancer, anon-small cell lung cancer, an ovarian cancer, a breast cancer, aprostate cancer, a pancreatic cancer, a hematological malignancy or arenal cell carcinoma. The cancer may be at an early, intermediate orlate stage.

In some embodiments, the anti-LAG-3 antibody molecule, e.g., theanti-LAG-3 antibody molecule described herein, alone or in combinationwith another immunomodulator (e.g., an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule), is used in combination with a JAK2inhibitor, e.g., CEP-701, INCB18424, CP-690550 (tasocitinib).

In some embodiments, the pharmaceutical composition described herein,alone or in combination with another immunomodulator (e.g., ananti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule), is used incombination with paclitaxel or a paclitaxel agent, e.g., TAXOL®,protein-bound paclitaxel (e.g., ABRAXANE®). Exemplary paclitaxel agentsinclude, but are not limited to, nanoparticle albumin-bound paclitaxel(ABRAXANE, marketed by Abraxis Bioscience), docosahexaenoic acidbound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX, marketed by Cell Therapeutic), the tumor-activatedprodrug (TAP), ANG105 (Angiopep-2 bound to three molecules ofpaclitaxel, marketed by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound tothe erbB2-recognizing peptide EC-1; see Li et al., Biopolymers (2007)87:225-230), and glucose-conjugated paclitaxel (e.g., 2′-paclitaxelmethyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic &Medicinal Chemistry Letters (2007) 17:617-620).

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” refersto radiation therapy delivered by a spatially confined radioactivematerial inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as 1-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Anti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), can be administered in combination with one or more of theexisting modalities for treating cancers, including, but not limited to:surgery; radiation therapy (e.g., external-beam therapy which involvesthree dimensional, conformal radiation therapy where the field ofradiation is designed, local radiation (e.g., radiation directed to apreselected target or organ), or focused radiation). Focused radiationcan be selected from the group consisting of stereotactic radiosurgery,fractionated stereotactic radiosurgery, and intensity-modulatedradiation therapy. The focused radiation can have a radiation sourceselected from the group consisting of a particle beam (proton),cobalt-60 (photon), and a linear accelerator (x-ray), e.g., as describedin WO 2012/177624.

In certain embodiments, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used with an antibody against aKiller-cell Immunoglobulin-like Receptor (also referred to herein as an“anti-KIR antibody”), a pan-KIR antibody, an anti-NKG2D antibody, and ananti-MICA antibody. In certain embodiments, the combination ofanti-LAG-3 antibody molecule, anti-PD-1 antibody molecule and anti-KIRantibody, pan-KIR antibody, anti-MICA antibody, or anti-NKG2D antibodydescribed herein is used to treat a cancer, e.g., a cancer as describedherein (e.g., a solid tumor, e.g., an advanced solid tumor).

In one embodiment, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used with a cellular immunotherapy(e.g., Provenge (e.g., Sipuleucel)), and optionally in combination withcyclophosphamide. In certain embodiments, the combination of anti-LAG-3antibody molecule, anti-PD-1 antibody molecule, Provenge and/orcyclophosphamide is used to treat a cancer, e.g., a cancer as describedherein (e.g., a prostate cancer, e.g., an advanced prostate cancer).

In another embodiment, anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used with a vaccine, e.g., adendritic cell renal carcinoma (DC-RCC) vaccine. In certain embodiments,the combination of anti-LAG-3 antibody molecule, anti-PD-1 antibodymolecule and/or the DC-RCC vaccine is used to treat a cancer, e.g., acancer as described herein (e.g., a renal carcinoma, e.g., metastaticrenal cell carcinoma (RCC)).

In one embodiment, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used in combination withchemotherapy to treat a lung cancer, e.g., non-small cell lung cancer.In one embodiment, the anti-LAG-3 antibody molecule is used withplatinum doublet therapy to treat lung cancer.

In yet another embodiment, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used to treat a renal cancer, e.g.,renal cell carcinoma (RCC) or metastatic RCC. The anti-LAG-3 antibodymolecule can be administered in combination with one or more of: animmune-based strategy (e.g., interleukin-2 or interferon-α), a targetedagent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF); aVEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitiniband pazopanib; an RNAi inhibitor), or an inhibitor of a downstreammediator of VEGF signaling, e.g., an inhibitor of the mammalian targetof rapamycin (mTOR), e.g., everolimus and temsirolimus.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), described herein for treatment of pancreatic cancer includes,but is not limited to, a chemotherapeutic agent, e.g., paclitaxel or apaclitaxel agent (e.g., a paclitaxel formulation such as TAXOL, analbumin-stabilized nanoparticle paclitaxel formulation (e.g., ABRAXANE)or a liposomal paclitaxel formulation); gemcitabine (e.g., gemcitabinealone or in combination with AXP107-11); other chemotherapeutic agentssuch as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicinhydrochloride, NC-6004, cisplatin, docetaxel (e.g., TAXOTERE), mitomycinC, ifosfamide; interferon; tyrosine kinase inhibitor (e.g., EGFRinhibitor (e.g., erlotinib, panitumumab, cetuximab, nimotuzumab);HER2/neu receptor inhibitor (e.g., trastuzumab); dual kinase inhibitor(e.g., bosutinib, saracatinib, lapatinib, vandetanib); multikinaseinhibitor (e.g., sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitor(e.g., bevacizumab, AV-951, brivanib); radioimmunotherapy (e.g., XR303);cancer vaccine (e.g., GVAX, survivin peptide); COX-2 inhibitor (e.g.,celecoxib); IGF-1 receptor inhibitor (e.g., AMG 479, MK-0646); mTORinhibitor (e.g., everolimus, temsirolimus); IL-6 inhibitor (e.g., CNTO328); cyclin-dependent kinase inhibitor (e.g., P276-00, UCN-01); AlteredEnergy Metabolism-Directed (AEMD) compound (e.g., CPI-613); HDACinhibitor (e.g., vorinostat); TRAIL receptor 2 (TR-2) agonist (e.g.,conatumumab); MEK inhibitor (e.g., AS703026, selumetinib, GSK1120212);Raf/MEK dual kinase inhibitor (e.g., RO5126766); Notch signalinginhibitor (e.g., MK0752); monoclonal antibody-antibody fusion protein(e.g., L19IL2); curcumin; HSP90 inhibitor (e.g., tanespimycin,STA-9090); rIL-2; denileukin diftitox; topoisomerase 1 inhibitor (e.g.,irinotecan, PEP02); statin (e.g., simvastatin); Factor VIIa inhibitor(e.g., PCI-27483); AKT inhibitor (e.g., RX-0201); hypoxia-activatedprodrug (e.g., TH-302); metformin hydrochloride, gamma-secretaseinhibitor (e.g., RO4929097); ribonucleotide reductase inhibitor (e.g.,3-AP); immunotoxin (e.g., HuC242-DM4); PARP inhibitor (e.g., KU-0059436,veliparib); CTLA-4 inhbitor (e.g., CP-675,206, ipilimumab); AdV-tktherapy; proteasome inhibitor (e.g., bortezomib (Velcade), NPI-0052);thiazolidinedione (e.g., pioglitazone); NPC-1C; Aurora kinase inhibitor(e.g., R763/AS703569), CTGF inhibitor (e.g., FG-3019); siG12D LODER; andradiation therapy (e.g., tomotherapy, stereotactic radiation, protontherapy), surgery, and a combination thereof. In certain embodiments, acombination of paclitaxel or a paclitaxel agent, and gemcitabine can beused with the anti-PD-1 antibody molecules described herein.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of small cell lung cancer includes, but is notlimited to, a chemotherapeutic agent, e.g., etoposide, carboplatin,cisplatin, oxaliplatin, irinotecan, topotecan, gemcitabine, liposomalSN-38, bendamustine, temozolomide, belotecan, NK012, FR901228,flavopiridol); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g.,erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor(e.g., sorafenib, sunitinib); VEGF inhibitor (e.g., bevacizumab,vandetanib); cancer vaccine (e.g., GVAX); Bcl-2 inhibitor (e.g.,oblimersen sodium, ABT-263); proteasome inhibitor (e.g., bortezomib(Velcade), NPI-0052), paclitaxel or a paclitaxel agent; docetaxel; IGF-1receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102,MK-0646); chloroquine; Aurora kinase inhibitor (e.g., MLN8237);radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g., tanespimycin,STA-9090); mTOR inhibitor (e.g., everolimus); Ep-CAM-/CD3-bispecificantibody (e.g., MT110); CK-2 inhibitor (e.g., CX-4945); HDAC inhibitor(e.g., belinostat); SMO antagonist (e.g., BMS 833923); peptide cancervaccine, and radiation therapy (e.g., intensity-modulated radiationtherapy (IMRT), hypofractionated radiotherapy, hypoxia-guidedradiotherapy), surgery, and combinations thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of non-small cell lung cancer includes, but isnot limited to, a chemotherapeutic agent, e.g., vinorelbine, cisplatin,docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin,liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium,azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium,sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g.,erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804,nimotuzumab, RO5083945), MET inhibitor (e.g., PF-02341066, ARQ 197),PI3K kinase inhibitor (e.g., XL147, GDC-0941), Raf/MEK dual kinaseinhibitor (e.g., RO5126766), PI3K/mTOR dual kinase inhibitor (e.g.,XL765), SRC inhibitor (e.g., dasatinib), dual inhibitor (e.g., BIBW2992, GSK1363089, ZD6474, AZD0530, AG-013736, lapatinib, MEHD7945A,linifanib), multikinase inhibitor (e.g., sorafenib, sunitinib,pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor(e.g., endostar, endostatin, bevacizumab, cediranib, BIBF 1120,axitinib, tivozanib, AZD2171), cancer vaccine (e.g., BLP25 liposomevaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein),Bcl-2 inhibitor (e.g., oblimersen sodium), proteasome inhibitor (e.g.,bortezomib, carfilzomib, NPI-0052, MLN9708), paclitaxel or a paclitaxelagent, docetaxel, IGF-1 receptor inhibitor (e.g., cixutumumab, MK-0646,OSI 906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor(e.g., tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (e.g.,everolimus, temsirolimus, ridaforolimus), Ep-CAM-/CD3-bispecificantibody (e.g., MT110), CK-2 inhibitor (e.g., CX-4945), HDAC inhibitor(e.g., MS 275, LBH589, vorinostat, valproic acid, FR901228), DHFRinhibitor (e.g., pralatrexate), retinoid (e.g., bexarotene, tretinoin),antibody-drug conjugate (e.g., SGN-15), bisphosphonate (e.g., zoledronicacid), cancer vaccine (e.g., belagenpumatucel-L), low molecular weightheparin (LMWH) (e.g., tinzaparin, enoxaparin), GSK1572932A, melatonin,talactoferrin, dimesna, topoisomerase inhibitor (e.g., amrubicin,etoposide, karenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (e.g.,MM-121, U3-1287), survivin inhibitor (e.g., YM155, LY2181308), eribulinmesylate, COX-2 inhibitor (e.g., celecoxib), pegfilgrastim, Polo-likekinase 1 inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist(e.g., CS-1008), CNGRC peptide (SEQ ID NO: 293)-TNF alpha conjugate,dichloroacetate (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550,PPAR-gamma agonist (e.g., CS-7017), gamma-secretase inhibitor (e.g.,RO4929097), epigenetic therapy (e.g., 5-azacitidine), nitroglycerin, MEKinhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g.,UCN-01), cholesterol-Fus1, antitubulin agent (e.g., E7389),farnesyl-OH-transferase inhibitor (e.g., lonafarnib), immunotoxin (e.g.,BB-10901, SS1 (dsFv) PE38), fondaparinux, vascular-disrupting agent(e.g., AVE8062), PD-L1 inhibitor (e.g., MDX-1105, MDX-1106),beta-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (e.g., GSK1120212),epothilone analog (e.g., ixabepilone), kinesin-spindle inhibitor (e.g.,4SC-205), telomere targeting agent (e.g., KML-001), P70 pathwayinhibitor (e.g., LY2584702), AKT inhibitor (e.g., MK-2206), angiogenesisinhibitor (e.g., lenalidomide), Notch signaling inhibitor (e.g.,OMP-21M18), radiation therapy, surgery, and combinations thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of ovarian cancer includes, but is not limitedto, a chemotherapeutic agent (e.g., paclitaxel or a paclitaxel agent;docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin;irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan,pemetrexed disodium, SJG-136, cyclophosphamide, etoposide, decitabine);ghrelin antagonist (e.g., AEZS-130), immunotherapy (e.g., APC8024,oregovomab, OPT-821), tyrosine kinase inhibitor (e.g., EGFR inhibitor(e.g., erlotinib), dual inhibitor (e.g., E7080), multikinase inhibitor(e.g., AZD0530, JI-101, sorafenib, sunitinib, pazopanib), ON 01910.Na),VEGF inhibitor (e.g., bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFRinhibitor (e.g., IMC-3G3), paclitaxel, topoisomerase inhibitor (e.g.,karenitecin, Irinotecan), HDAC inhibitor (e.g., valproate, vorinostat),folate receptor inhibitor (e.g., farletuzumab), angiopoietin inhibitor(e.g., AMG 386), epothilone analog (e.g., ixabepilone), proteasomeinhibitor (e.g., carfilzomib), IGF-1 receptor inhibitor (e.g., OSI 906,AMG 479), PARP inhibitor (e.g., veliparib, AG014699, iniparib, MK-4827),Aurora kinase inhibitor (e.g., MLN8237, ENMD-2076), angiogenesisinhibitor (e.g., lenalidomide), DHFR inhibitor (e.g., pralatrexate),radioimmunotherapeutic agent (e.g., Hu3S193), statin (e.g., lovastatin),topoisomerase 1 inhibitor (e.g., NKTR-102), cancer vaccine (e.g., p53synthetic long peptides vaccine, autologous OC-DC vaccine), mTORinhibitor (e.g., temsirolimus, everolimus), BCR/ABL inhibitor (e.g.,imatinib), ET-A receptor antagonist (e.g., ZD4054), TRAIL receptor 2(TR-2) agonist (e.g., CS-1008), HGF/SF inhibitor (e.g., AMG 102),EGEN-001, Polo-like kinase 1 inhibitor (e.g., BI 6727), gamma-secretaseinhibitor (e.g., RO4929097), Wee-1 inhibitor (e.g., MK-1775),antitubulin agent (e.g., vinorelbine, E7389), immunotoxin (e.g.,denileukin diftitox), SB-485232, vascular-disrupting agent (e.g.,AVE8062), integrin inhibitor (e.g., EMD 525797), kinesin-spindleinhibitor (e.g., 4SC-205), revlimid, HER2 inhibitor (e.g., MGAH22),ErrB3 inhibitor (e.g., MM-121), radiation therapy; and combinationsthereof.

In one exemplary embodiment, the anti-LAG-3 antibody molecule, alone orin combination with another immunomodulator (e.g., an anti-PD-1,anti-PD-L1 or anti-TIM-3 antibody molecule), is used to treat a myeloma,alone or in combination with one or more of: chemotherapy or otheranti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), HSCT(Cook, R. (2008) J Manag Care Pharm. 14 (7 Suppl):19-25), an anti-TIM3antibody (Hallett, W H D et al. (2011) J of American Society for Bloodand Marrow Transplantation 17(8):1133-145), tumor antigen-pulseddendritic cells, fusions (e.g., electrofusions) of tumor cells anddendritic cells, or vaccination with immunoglobulin idiotype produced bymalignant plasma cells (reviewed in Yi, Q. (2009) Cancer J.15(6):502-10).

In yet another embodiment, the anti-LAG-3 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-PD-1, anti-PD-L1or anti-TIM-3 antibody molecule), is used to treat a renal cancer, e.g.,renal cell carcinoma (RCC) or metastatic RCC. The anti-PD-1 antibodymolecule can be administered in combination with one or more of: animmune-based strategy (e.g., interleukin-2 or interferon-α), a targetedagent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF,e.g., bevacizumab (Rini, B. I. et al. (2010) J. Clin. Oncol.28(13):2137-2143)); a VEGF tyrosine kinase inhibitor such as sunitinib,sorafenib, axitinib and pazopanib (reviewed in Pal. S. K. et al. (2014)Clin. Advances in Hematology & Oncology 12(2):90-99)); an RNAiinhibitor), or an inhibitor of a downstream mediator of VEGF signaling,e.g., an inhibitor of the mammalian target of rapamycin (mTOR), e.g.,everolimus and temsirolimus (Hudes, G. et al. (2007) N. Engl. J. Med.356(22):2271-2281, Motzer, R. J. et al. (2008) Lancet 372: 449-456).

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of chronic myelogenous leukemia (AML) accordingto the invention includes, but is not limited to, a chemotherapeutic(e.g., cytarabine, hydroxyurea, clofarabine, melphalan, thiotepa,fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine,azacitidine, cyclophosphamide, cladribine, topotecan), tyrosine kinaseinhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON01910.Na, dual inhibitor (e.g., dasatinib, bosutinib), multikinaseinhibitor (e.g., DCC-2036, ponatinib, sorafenib, sunitinib,RGB-286638)), interferon alfa, steroids, apoptotic agent (e.g.,omacetaxine mepesuccinat), immunotherapy (e.g., allogeneic CD4+ memoryTh1-like T cells/microparticle-bound anti-CD3/anti-CD28, autologouscytokine induced killer cells (CIK), AHN-12), CD52 targeting agent(e.g., alemtuzumab), HSP90 inhibitor (e.g., tanespimycin, STA-9090,AUY922, XL888), mTOR inhibitor (e.g., everolimus), SMO antagonist (e.g.,BMS 833923), ribonucleotide reductase inhibitor (e.g., 3-AP), JAK-2inhibitor (e.g., INCB018424), Hydroxychloroquine, retinoid (e.g.,fenretinide), cyclin-dependent kinase inhibitor (e.g., UCN-01), HDACinhibitor (e.g., belinostat, vorinostat, JNJ-26481585), PARP inhibitor(e.g., veliparib), MDM2 antagonist (e.g., RO5045337), Aurora B kinaseinhibitor (e.g., TAK-901), radioimmunotherapy (e.g.,actinium-225-labeled anti-CD33 antibody HuM195), Hedgehog inhibitor(e.g., PF-04449913), STAT3 inhibitor (e.g., OPB-31121), KB004, cancervaccine (e.g., AG858), bone marrow transplantation, stem celltransplantation, radiation therapy, and combinations thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of chronic lymphocytic leukemia (CLL) includes,but is not limited to, a chemotherapeutic agent (e.g., fludarabine,cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine,chlorambucil, busulfan, gemcitabine, melphalan, pentostatin,mitoxantrone, 5-azacytidine, pemetrexed disodium), tyrosine kinaseinhibitor (e.g., EGFR inhibitor (e.g., erlotinib), BTK inhibitor (e.g.,PCI-32765), multikinase inhibitor (e.g., MGCD265, RGB-286638), CD-20targeting agent (e.g., rituximab, ofatumumab, RO5072759, LFB-R603), CD52targeting agent (e.g., alemtuzumab), prednisolone, darbepoetin alfa,lenalidomide, Bcl-2 inhibitor (e.g., ABT-263), immunotherapy (e.g.,allogeneic CD4+ memory Th1-like T cells/microparticle-boundanti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK)),HDAC inhibitor (e.g., vorinostat, valproic acid, LBH589, JNJ-26481585,AR-42), XIAP inhibitor (e.g., AEG35156), CD-74 targeting agent (e.g.,milatuzumab), mTOR inhibitor (e.g., everolimus), AT-101, immunotoxin(e.g., CAT-8015, anti-Tac(Fv)-PE38 (LMB-2)), CD37 targeting agent (e.g.,TRU-016), radioimmunotherapy (e.g., 131-tositumomab),hydroxychloroquine, perifosine, SRC inhibitor (e.g., dasatinib),thalidomide, PI3K delta inhibitor (e.g., CAL-101), retinoid (e.g.,fenretinide), MDM2 antagonist (e.g., RO5045337), plerixafor, Aurorakinase inhibitor (e.g., MLN8237, TAK-901), proteasome inhibitor (e.g.,bortezomib), CD-19 targeting agent (e.g., MEDI-551, MOR208), MEKinhibitor (e.g., ABT-348), JAK-2 inhibitor (e.g., INCB018424),hypoxia-activated prodrug (e.g., TH-302), paclitaxel or a paclitaxelagent, HSP90 inhibitor, AKT inhibitor (e.g., MK2206), HMG-CoA inhibitor(e.g., simvastatin), GNKG186, radiation therapy, bone marrowtransplantation, stem cell transplantation, and a combination thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of acute lymphocytic leukemia (ALL) includes,but is not limited to, a chemotherapeutic agent (e.g., prednisolone,dexamethasone, vincristine, asparaginase, daunorubicin,cyclophosphamide, cytarabine, etoposide, thioguanine, mercaptopurine,clofarabine, liposomal annamycin, busulfan, etoposide, capecitabine,decitabine, azacitidine, topotecan, temozolomide), tyrosine kinaseinhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON01910.Na, multikinase inhibitor (e.g., sorafenib)), CD-20 targetingagent (e.g., rituximab), CD52 targeting agent (e.g., alemtuzumab), HSP90inhibitor (e.g., STA-9090), mTOR inhibitor (e.g., everolimus,rapamycin), JAK-2 inhibitor (e.g., INCB018424), HER2/neu receptorinhibitor (e.g., trastuzumab), proteasome inhibitor (e.g., bortezomib),methotrexate, asparaginase, CD-22 targeting agent (e.g., epratuzumab,inotuzumab), immunotherapy (e.g., autologous cytokine induced killercells (CIK), AHN-12), blinatumomab, cyclin-dependent kinase inhibitor(e.g., UCN-01), CD45 targeting agent (e.g., BC8), MDM2 antagonist (e.g.,RO5045337), immunotoxin (e.g., CAT-8015, DT2219ARL), HDAC inhibitor(e.g., JNJ-26481585), JVRS-100, paclitaxel or a paclitaxel agent, STAT3inhibitor (e.g., OPB-31121), PARP inhibitor (e.g., veliparib), EZN-2285,radiation therapy, steroid, bone marrow transplantation, stem celltransplantation, or a combination thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of acute myeloid leukemia (AML) includes, butis not limited to, a chemotherapeutic agent (e.g., cytarabine,daunorubicin, idarubicin, clofarabine, decitabine, vosaroxin,azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine,azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g.,imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g.,midostaurin, SU 11248, quizartinib, sorafinib)), immunotoxin (e.g.,gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g.,vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g., everolimus), SRCinhibitor (e.g., dasatinib), HSP90 inhbitor (e.g., STA-9090), retinoid(e.g., bexarotene, Aurora kinase inhibitor (e.g., BI 811283), JAK-2inhibitor (e.g., INCB018424), Polo-like kinase inhibitor (e.g., BI6727), cenersen, CD45 targeting agent (e.g., BC8), cyclin-dependentkinase inhibitor (e.g., UCN-01), MDM2 antagonist (e.g., RO5045337), mTORinhibitor (e.g., everolimus), LY573636-sodium, ZRx-101, MLN4924,lenalidomide, immunotherapy (e.g., AHN-12), histamine dihydrochloride,radiation therapy, bone marrow transplantation, stem celltransplantation, and a combination thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of multiple myeloma (MM) includes, but is notlimited to, a chemotherapeutic agent (e.g., melphalan, amifostine,cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine,adriamycin, SyB L-0501), thalidomide, lenalidomide, dexamethasone,prednisone, pomalidomide, proteasome inhibitor (e.g., bortezomib,carfilzomib, MLN9708), cancer vaccine (e.g., GVAX), CD-40 targetingagent (e.g., SGN-40, CHIR-12.12), perifosine, zoledronic acid,Immunotherapy (e.g., MAGE-A3, NY-ESO-1, HuMax-CD38), HDAC inhibitor(e.g., vorinostat, LBH589, AR-42), aplidin, cycline-dependent kinaseinhibitor (e.g., PD-0332991, dinaciclib), arsenic trioxide, CB3304,HSP90 inhibitor (e.g., KW-2478), tyrosine kinase inhibitor (e.g., EGFRinhibitor (e.g., cetuximab), multikinase inhibitor (e.g., AT9283)), VEGFinhibitor (e.g., bevacizumab), plerixafor, MEK inhibitor (e.g.,AZD6244), IPH2101, atorvastatin, immunotoxin (e.g., BB-10901), NPI-0052,radioimmunotherapeutic (e.g., yttrium Y 90 ibritumomab tiuxetan), STAT3inhibitor (e.g., OPB-31121), MLN4924, Aurora kinase inhibitor (e.g.,ENMD-2076), IMGN901, ACE-041, CK-2 inhibitor (e.g., CX-4945), radiationtherapy, bone marrow transplantation, stem cell transplantation, and acombination thereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecule, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of prostate cancer includes, but is not limitedto, a chemotherapeutic agent (e.g., docetaxel, carboplatin,fludarabine), abiraterone, hormonal therapy (e.g., flutamide,bicalutamide, nilutamide, cyproterone acetate, ketoconazole,aminoglutethimide, abarelix, degarelix, leuprolide, goserelin,triptorelin, buserelin), tyrosine kinase inhibitor (e.g., dual kinaseinhibitor (e.g., lapatanib), multikinase inhibitor (e.g., sorafenib,sunitinib)), VEGF inhibitor (e.g., bevacizumab), TAK-700, cancer vaccine(e.g., BPX-101, PEP223), lenalidomide, TOK-001, IGF-1 receptor inhibitor(e.g., cixutumumab), TRC 105, Aurora A kinase inhibitor (e.g., MLN8237),proteasome inhibitor (e.g., bortezomib), OGX-011, radioimmunotherapy(e.g., HuJ591-GS), HDAC inhibitor (e.g., valproic acid, SB939, LBH589),hydroxychloroquine, mTOR inhibitor (e.g., everolimus), dovitiniblactate, diindolylmethane, efavirenz, OGX-427, genistein, IMC-3G3,bafetinib, CP-675,206, radiation therapy, surgery, or a combinationthereof.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of HNSCC includes, but is not limited to, oneor both of Compound A8 as described herein (or a compound described inPCT Publication No. WO2010/029082) and cetuximab (e.g., Erbitux,marketed by BMS). In some embodiments, the therapeutic (e.g., theCompound A8 or compound related to A8) is a PI3K modulator, e.g., a PI3Kinhibitor. In some embodiments, the therapeutic (e.g., cetuximab)modulates, e.g., inhibits, EGFR. In some embodiments, the cancer has, oris identified as having, elevated levels or activity of PI3K or EGFRcompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of gastric cancer, e.g., MSI-high and/or EBV+gastric cancer, includes, but is not limited to, Compound A8 asdescribed herein (or a compound described in PCT Publication No.WO2010/029082). In some embodiments, the therapeutic (e.g., the CompoundA8 or compound related to A8) is a PI3K modulator, e.g., a PI3Kinhibitor. In some embodiments, the cancer has, or is identified ashaving, elevated levels or activity of PI3K compared to a control cellor reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of gastric cancer, e.g., MSI-high and/orRNF43-inactivated gastric cancer, includes, but is not limited to,Compound A28 as described herein (or a compound described in PCTPublication No. WO2010/101849). In some embodiments, the therapeutic(e.g., the Compound A28 or compound related to A28) is a modulator,e.g., inhibitor, of porcupine. In some embodiments, the cancer has, oris identified as having, elevated levels or activity of porcupinecompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of GI stromal tumor (GIST), includes, but isnot limited to, Compound A16 as described herein (or a compounddescribed in PCT Publication No. WO1999/003854). In some embodiments,the therapeutic (e.g., the Compound A16 or compound related to A16) is amodulator, e.g., inhibitor, of a tyrosine kinase. In some embodiments,the cancer has, or is determined to have, elevated levels or activity ofa tyrosine kinase compared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of NSCLC, e.g., squamous or adenocarcinoma,includes, but is not limited to, one or both of Compound A17 asdescribed herein (or a compound described in U.S. Pat. Nos. 7,767,675and 8,420,645) and Compound A23 as described herein (or a compounddescribed in PCT Publication No. WO2003/077914). In some embodiments,the compound (e.g., the Compound A17 or compound related to A17)modulates, e.g., inhibits, c-MET. In some embodiments, the compound(e.g., the Compound A23 or compound related to A23) modulates, e.g.,inhibits, Alk. In some embodiments, the cancer has, or is determined tohave, elevated levels or activity of one or both of c-MET or Alkcompared to a control cell or reference value. In some embodiments, thecancer has, or is identified as having, a mutation in EGFR.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of melanoma (e.g., NRAS melanoma) includes, butis not limited to, one or both of Compound A24 as described herein (or acompound described in U.S. Pat. Nos. 8,415,355 and 8,685,980) andCompound A34 as described herein (or a compound described in PCTPublication No. WO2003/077914). In some embodiments, the compound (e.g.,the Compound A24 or compound related to A24) modulates, e.g., inhibits,one or more of JAK and CDK4/6. In some embodiments, the compound (e.g.,the Compound A34 or compound related to A34) modulates, e.g., inhibits,MEK. In some embodiments, the cancer has, or is identified as having,elevated levels or activity of one or more of JAK, CDK4/6, and MEKcompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of melanoma (e.g., NRAS melanoma) includes, butis not limited to, one or both of Compound A29 as described herein (or acompound described in PCT Publication No. WO2011/025927) and CompoundA34 as described herein (or a compound described in PCT Publication No.WO2003/077914). In some embodiments, the compound (e.g., the CompoundA29 or compound related to A29) modulates, e.g., inhibits, BRAF. In someembodiments, the compound (e.g., the Compound A34 or compound related toA34) modulates, e.g., inhibits, MEK. In some embodiments, the cancerhas, or is identified as having, elevated levels or activity of one orboth of BRAF and MEK compared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of squamous NSCLC includes, but is not limitedto, Compound A5 as described herein (or a compound described in U.S.Pat. No. 8,552,002). In some embodiments, the compound (e.g., theCompound A5 or compound related to A5) modulates, e.g., inhibits, FGFR.In some embodiments, the cancer has, or is identified as having,elevated levels or activity of FGFR compared to a control cell orreference value.

An example of suitable therapeutics for use in combination with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of colorectal cancer includes, but is notlimited to, one or both of Compound A29 as described herein (or acompound PCT Publication No. WO2011/025927) and cetuximab (e.g.,Erbitux, marketed by BMS). In some embodiments, the therapeutic (e.g.,the Compound A29 or compound related to A29) modulates, e.g., inhibits,BRAF. In some embodiments, the therapeutic (e.g., cetuximab) modulates,e.g., inhibits EGFR. In some embodiments, the cancer has, or isidentified as having, elevated levels or activity of BRAF or EGFRcompared to a control cell or reference value.

This disclosure also provides a method of treating cancer with CompoundA8, cetuximab, and a LAG-3 antibody molecule (optionally in combinationwith a PD-1 antibody molecule or TIM-3 antibody molecule). In someembodiments, the patient is first treated with Compound A8 andcetuximab. This treatment continues for an amount of time, e.g., apredetermined amount of time, e.g., about 1, 2, 4, 6, 8, 10, or 12months. Next, the LAG-3 antibody molecule (optionally in combinationwith a PD-1 antibody molecule or TIM-3 antibody molecule) isadministered. The LAG-3 antibody can optionally be administered incombination with cetuximab.

In some embodiments, the patient is first treated with all three ofCompound A8, cetuximab, and a LAG-3 antibody molecule (optionally incombination with a PD-1 antibody molecule or TIM-3 antibody molecule).This treatment continues for an amount of time, e.g., a predeterminedamount of time, e.g., about 6, 8, 10, or 12 months. Next, the CompoundA8 and/or cetuximab can be tapered off, so that the maintenance phaseinvolves treatment with the LAG-3 antibody molecule (e.g., as amonotherapy, or in combination with a PD-1 antibody molecule or TIM-3antibody molecule) but not Compound A8 or cetuximab.

In other embodiments, the three compounds (Compound A8, cetuximab, and aLAG-3 antibody molecule, optionally in combination with a PD-1 antibodymolecule or TIM-3 antibody molecule) are given sequentially at theoutset of the treatment. For instance, Compound A8 and cetuximab can begiven first, as described above. Next, the LAG-3 antibody molecule(optionally in combination with a PD-1 antibody molecule or TIM-3antibody molecule) is added to the regimen. Next, the Compound A8 and/orcetuximab can be tapered off as described above.

Exemplary doses for the three (or more) agent regimens are as follows.The LAG-3 antibody molecule can be administered, e.g., at a dose ofabout 1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg,about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg. In someembodiments, the Compound A8 is administered at a dose of approximately200-300, 300-400, or 200-400 mg. In some embodiments, the cetuximab isadministered at a 400 mg/m2 initial dose as a 120-minute intravenousinfusion followed by 250 mg/m2 weekly infused over 60 minutes. Inembodiments, one or more of the Compound A8, cetuximab, and LAG-3antibody molecule is administered at a dose that is lower than the doseat which that agent is typically administered as a monotherapy, e.g.,about 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or80-90% lower than the dose at which that agent is typically administeredas a monotherapy. In embodiments, the one or more of the Compound A8,cetuximab, and LAG-3 antibody molecule is administered at a dose that islower than the dose of that agent recited in this paragraph, e.g., about0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90%lower than the dose of that agent recited in this paragraph. In certainembodiments, the concentration of the Compound A8 that is required toachieve inhibition, e.g., growth inhibition, is lower when the CompoundA8 is administered in combination with one or both of the cetuximab andLAG-3 antibody molecule than when the Compound A8 is administeredindividually. In certain embodiments, the concentration of the cetuximabthat is required to achieve inhibition, e.g., growth inhibition, islower when the cetuximab is administered in combination with one or bothof the Compound A8 and LAG-3 antibody molecule than when the cetuximabis administered individually. In certain embodiments, the concentrationof the LAG-3 antibody molecule that is required to achieve inhibition,e.g., growth inhibition, is lower when the LAG-3 antibody molecule isadministered in combination with one or both of the cetuximab andCompound A8 than when the LAG-3 antibody molecule is administeredindividually.

Additionally disclosed herein is a method of treating cancer with theanti-LAG-3 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), and a targeted anti-cancer agent, e.g., an agent that targetsone or more proteins. In some embodiments, the anti-LAG-3 antibodymolecule (and optionally other immunomodulator(s)) are administeredfirst, and the targeted anti-cancer agent is administered second. Thelength of time between administration of the anti-LAG-3 antibodymolecule and the targeted anti-cancer agent can be, e.g., 10, 20, or 30minutes, 1, 2, 4, 6, or 12 hours, or 1, 2, 3, 4, 5, 6, or 7 days, or anyspan of time within this range. In certain embodiments, the anti-LAG-3antibody molecule is administered repeatedly over a period of time(e.g., 1, 2, 3, 4, 5, or 6 days, or 1, 2, 4, 8, 12, 16, or 20 weeks, orany span of time within this range) before the targeted anti-canceragent is administered. In other embodiments, the anti-LAG-3 antibodymolecule and the targeted anti-cancer agent are administered atsubstantially the same time.

Infectious Diseases

Other methods of the invention are used to treat patients that have beenexposed to particular toxins or pathogens. Accordingly, another aspectof the invention provides a method of treating an infectious disease ina subject comprising administering to the subject an anti-LAG-3 antibodymolecule, such that the subject is treated for the infectious disease.

In the treatment of infection (e.g., acute and/or chronic),administration of the anti-LAG-3 antibody molecules (alone or incombination with an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule) can be combined with conventional treatments in addition to orin lieu of stimulating natural host immune defenses to infection.Natural host immune defenses to infection include, but are not limitedto inflammation, fever, antibody-mediated host defense,T-lymphocyte-mediated host defenses, including lymphokine secretion andcytotoxic T-cells (especially during viral infection), complementmediated lysis and opsonization (facilitated phagocytosis), andphagocytosis. The ability of the anti-LAG-3 antibody molecules toreactivate dysfunctional T-cells would be useful to treat chronicinfections, in particular those in which cell-mediated immunity isimportant for complete recovery.

Similar to its application to tumors as discussed above, antibodymediated LAG-3 blockade can be used alone, or as an adjuvant, incombination with vaccines, to stimulate the immune response topathogens, toxins, and self-antigens. Examples of pathogens for whichthis therapeutic approach may be particularly useful, include pathogensfor which there is currently no effective vaccine, or pathogens forwhich conventional vaccines are less than completely effective. Theseinclude, but are not limited to Hepatitis (A, B, and C), Influenza, HIV,Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, PseudomonasAeruginosa. LAG-3 blockade is particularly useful against establishedinfections by agents such as HIV that present altered antigens over thecourse of the infections. These novel epitopes are recognized as foreignat the time of anti-human LAG-3 administration, thus provoking a strongT cell response that is not dampened by negative signals through LAG-3.

Viruses

For infections resulting from viral causes, the anti-LAG-3 antibodymolecules (alone or in combination with an anti-PD-1, anti-PD-L1 oranti-TIM-3 antibody molecule) can be combined by applicationsimultaneous with, prior to or subsequent to application of standardtherapies for treating viral infections. Such standard therapies varydepending upon type of virus, although in almost all cases,administration of human serum containing antibodies (e.g., IgA, IgG)specific to the virus can be effective.

Some examples of pathogenic viruses causing infections treatable bymethods include hepatitis (A, B, or C), influenza virus (A, B, or C),HIV, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, CMV, Epstein Barrvirus), adenovirus, flaviviruses, echovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus,measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus,dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus,JC virus and arboviral encephalitis virus.

In one embodiment, the infection is an influenza infection. Influenzainfection can result in fever, cough, myalgia, headache and malaise,which often occur in seasonal epidemics. Influenza is also associatedwith a number of postinfectious disorders, such as encephalitis,myopericarditis, Goodpasture's syndrome, and Reye's syndrome. Influenzainfection also suppresses normal pulmonary antibacterial defenses, suchthat patient's recovering from influenza have an increased risk ofdeveloping bacterial pneumonia. Influenza viral surface proteins showmarked antigenic variation, resulting from mutation and recombination.Thus, cytolytic T lymphocytes are the host's primary vehicle for theelimination of virus after infection. Influenza is classified into threeprimary types: A, B and C. Influenza A is unique in that it infects bothhumans and many other animals (e.g., pigs, horses, birds and seals) andis the principal cause of pandemic influenza. Also, when a cell isinfected by two different influenza A strains, the segmented RNA genomesof two parental virus types mix during replication to create a hybridreplicant, resulting in new epidemic strains. Influenza B does notreplicate in animals and thus has less genetic variation and influenza Chas only a single serotype.

Most conventional therapies are palliatives of the symptoms resultingfrom infection, while the host's immune response actually clears thedisease. However, certain strains (e.g., influenza A) can cause moreserious illness and death. Influenza A may be treated both clinicallyand prophylactically by the administration of the cyclic aminesinhibitors amantadine and rimantadine, which inhibit viral replication.However, the clinical utility of these drugs is limited due to therelatively high incidence of adverse reactions, their narrow anti-viralspectrum (influenza A only), and the propensity of the virus to becomeresistant. The administration of serum IgG antibody to the majorinfluenza surface proteins, hemagglutinin and neuraminidase can preventpulmonary infection, whereas mucosal IgA is required to preventinfection of the upper respiratory tract and trachea. The most effectivecurrent treatment for influenza is vaccination with the administrationof virus inactivated with formalin or β-propiolactone. In oneembodiment, the anti-LAG-3 antibody molecule is administered incombination with an influenza antigen or vaccine.

In another embodiment, the infection is a hepatitis infection, e.g., aHepatitis B or C infection.

Hepatitis B virus (HB-V) is the most infectious known bloodbornepathogen. It is a major cause of acute and chronic hepatitis and hepaticcarcinoma, as well as life-long, chronic infection. Following infection,the virus replicates in hepatocytes, which also then shed the surfaceantigen HBsAg. The detection of excessive levels of HBsAg in serum isused a standard method for diagnosing a hepatitis B infection. An acuteinfection may resolve or it can develop into a chronic persistentinfection. Current treatments for chronic HBV include α-interferon,which increases the expression of class I human leukocyte antigen (HLA)on the surface of hepatocytes, thereby facilitating their recognition bycytotoxic T lymphocytes. Additionally, the nucleoside analogsganciclovir, famciclovir and lamivudine have also shown some efficacy inthe treatment of HBV infection in clinical trials. Additional treatmentsfor HBV include pegylated a-interferon, adenfovir, entecavir andtelbivudine. While passive immunity can be conferred through parentaladministration of anti-HBsAg serum antibodies, vaccination withinactivated or recombinant HBsAg also confers resistance to infection.The anti-LAG-3 antibody molecule (alone or in combination with ananti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) may be combinedwith conventional treatments for hepatitis B infections for therapeuticadvantage. In one embodiment, the anti-LAG-3 antibody molecule isadministered in combination with a hepatitis B antigen or vaccine, andoptionally in combination with an aluminum-containing adjuvant.

Hepatitis C virus (HC-V) infection may lead to a chronic form ofhepatitis, resulting in cirrosis. While symptoms are similar toinfections resulting from Hepatitis B, in distinct contrast to HB-V,infected hosts can be asymptomatic for 10-20 years. The anti-LAG-3antibody molecule can be administered as a monotherapy (or incombination with an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule), or all of the foregoing can be combined with the standard ofcare for hepatitis C infection. For example, the anti-LAG-3 antibodymolecule can be administered with one or more of Sovaldi (sofosbuvir)Olysio (simeprevir), plus ribavirin or pegylated interferon. Althoughregimens that include Incivek (telaprevir) or Victrelis (boceprevir)plus ribavirin and pegylated interferon are also approved, they areassociated with increased side effects and longer duration of treatmentand are therefore not considered preferred regimens.

Conventional treatment for HC-V infection includes the administration ofa combination of α-interferon and ribavirin. A promising potentialtherapy for HC-V infection is the protease inhibitor telaprevir(VX-960). Additional treatments include: anti-PD-1 antibody (e.g.,MDX-1106, Medarex), bavituximab (an antibody that binds anionicphospholipid phosphatidylserine in a B2-glycoprotein I dependent manner,Peregrine Pharmaceuticals), anti-HPV viral coat protein E2antibod(y)(ies) (e.g., ATL 6865−Ab68+Ab65, XTL Pharmaceuticals) andCivacir® (polyclonal anti-HCV human immune globulin). The anti-LAG-3antibody molecules may be combined with one or more of these treatmentsfor hepatitis C infections for therapeutic advantage. Protease,polymerase and NS5A inhibitors which may be used in combination with theanti-LAG-3 antibody molecules to specifically treat Hepatitis Cinfection include those described in US 2013/0045202, incorporatedherein by reference.

In another embodiment, the infection is a measles virus. After anincubation of 9-11 days, hosts infected with the measles virus developfever, cough, coryza and conjunctivitis. Within 1-2 days, anerythematous, maculopapular rash develop, which quickly spreads over theentire body. Because infection also suppresses cellular immunity, thehost is at greater risk for developing bacterial superinfections,including otitis media, pneumonia and postinfectious encephalomyelitis.Acute infection is associated with significant morbidity and mortality,especially in malnourished adolescents.

Treatment for measles includes the passive administration of pooledhuman IgG, which can prevent infection in non-immune subjects, even ifgiven up to one week after exposure. However, prior immunization withlive, attenuated virus is the most effective treatment and preventsdisease in more than 95% of those immunized. As there is one serotype ofthis virus, a single immunization or infection typically results inprotection for life from subsequent infection.

In a small proportion of infected hosts, measles can develop into SSPE,which is a chronic progressive neurologic disorder resulting from apersistent infection of the central nervous system. SSPE is caused byclonal variants of measles virus with defects that interfere with virionassembly and budding. For these patients, reactivation of T-cells withthe anti-LAG-3 antibody molecule so as to facilitate viral clearancewould be desirable.

In another embodiment, the infection is HIV. HIV attacks CD4+ cells,including T-lymphocytes, monocyte-macrophages, follicular dendriticcells and Langerhan's cells, and CD4+ helper/inducer cells are depleted.As a result, the host acquires a severe defect in cell-mediatedimmunity. Infection with HIV results in AIDS in at least 50% ofindividuals, and is transmitted via sexual contact, administration ofinfected blood or blood products, artificial insemination with infectedsemen, exposure to blood-containing needles or syringes and transmissionfrom an infected mother to infant during childbirth.

A host infected with HIV may be asymptomatic, or may develop an acuteillness that resembling mononucleosis—fever, headache, sore throat,malaise and rash. Symptoms can progress to progressive immunedysfunction, including persistent fever, night sweats, weight loss,unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpeszoster, oral candidiasis and oral hairy leukoplakia. Opportunisticinfections by a host of parasites are common in patients whoseinfections develop into AIDS.

Treatments for HIV include antiviral therapies including nucleosideanalogs, zidovudine (AST) either alone or in combination with didanosineor zalcitabine, dideoxyinosine, dideoxycytidine, lamidvudine, stavudine;reverse transcriptive inhibitors such as delavirdine, nevirapine,loviride, and proteinase inhibitors such as saquinavir, ritonavir,indinavir and nelfinavir. The anti-LAG-3 antibody molecule (alone or incombination with an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule) may be combined with conventional treatments for HIVinfections for therapeutic advantage.

In another embodiment, the infection is a Cytomegalovirus (CMV). CMVinfection is often associated with persistent, latent and recurrentinfection. CMV infects and remains latent in monocytes andgranulocyte-monocyte progenitor cells. The clinical symptoms of CMVinclude mononucleosis-like symptoms (i.e., fever, swollen glands,malaise), and a tendency to develop allergic skin rashes to antibiotics.The virus is spread by direct contact. The virus is shed in the urine,saliva, semen and to a lesser extent in other body fluids. Transmissioncan also occur from an infected mother to her fetus or newborn and byblood transfusion and organ transplants. CMV infection results ingeneral impairment of cellular immunity, characterized by impairedblastogenic responses to nonspecific mitogens and specific CMV antigens,diminished cytotoxic ability and elevation of CD8 lymphocyte number ofCD4+ lymphocytes.

Treatments of CMV infection include the anti-virals ganciclovir,foscarnet and cidovir, but these drugs are typically only prescribed inimmunocompromised patients. The anti-LAG-3 antibody molecule (alone orin combination with an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule) may be combined with conventional treatments forcytomegalovirus infections for therapeutic advantage.

In another embodiment, the infection is Epstein-Barr virus (EBV). EBVcan establish persistent and latent infections and primarily attacks Bcells. Infection with EBV results in the clinical condition ofinfectious mononucleosis, which includes fever, sore throat, often withexudate, generalized lymphadenopathy and splenomegaly. Hepatitis is alsopresent, which can develop into jaundice.

While typical treatments for EBV infections are palliative of symptoms,EBV is associated with the development of certain cancers such asBurkitt's lymphoma and nasopharyngeal cancer. Thus, clearance of viralinfection before these complications result would be of great benefit.The anti-LAG-3 antibody molecule (alone or in combination with ananti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) may be combinedwith conventional treatments for Epstein-Barr virus infections fortherapeutic advantage.

In another embodiment, the infection is Herpes simplex virus (HSV). HSVis transmitted by direct contact with an infected host. A directinfection may be asymptomatic, but typically result in blisterscontaining infectious particles. The disease manifests as cycles ofactive periods of disease, in which lesions appear and disappear as theviral latently infect the nerve ganglion for subsequent outbreaks.Lesions may be on the face, genitals, eyes and/or hands. In some case,an infection can also cause encephalitis.

Treatments for herpes infections are directed primarily to resolving thesymptomatic outbreaks, and include systemic antiviral medicines such as:acyclovir (e.g., Zovirax®), valaciclovir, famciclovir, penciclovir, andtopical medications such as docosanol (Abreva®), tromantadine andzilactin. The clearance of latent infections of herpes would be of greatclinical benefit. The anti-LAG-3 antibody molecule (alone or incombination with an anti-PD-1, anti-PD-L1 or anti-TIM-3 antibodymolecule) may be combined with conventional treatments for herpes virusinfections for therapeutic advantage.

In another embodiment, the infection is Human T-lymphotrophic virus(HTLV-1, HTLV-2). HTLV is transmitted via sexual contact, breast feedingor exposure to contaminated blood. The virus activates a subset of T_(H)cells called Th1 cells, resulting in their overproliferation andoverproduction of Th1 related cytokines (e.g., IFN-γ and TNF-α). This inturn results in a suppression of Th2 lymphocytes and reduction of Th2cytokine production (e.g., IL-4, IL-5, IL-10 and IL-13), causing areduction in the ability of an infected host to mount an adequate immuneresponse to invading organisms requiring a Th2-dependent response forclearance (e.g., parasitic infections, production of mucosal and humoralantibodies).

HTLV infections cause lead to opportunistic infections resulting inbronchiectasis, dermatitis and superinfections with Staphylococcus spp.and Strongyloides spp. resulting in death from polymicrobial sepsis.HTLV infection can also lead directly to adult T-cell leukemia/lymphomaand progressive demyelinating upper motor neuron disease known asHAM/TSP. The clearance of HTLV latent infections would be of greatclinical benefit. The anti-LAG-3 antibody molecules (alone or incombination with an anti-PD-1, anti-PD-L or anti-TIM-3 antibodymolecule) may be combined with conventional treatments for HTLVinfections for therapeutic advantage.

In another embodiment, the infection is Human papilloma virus (HPV). HPVprimarily affects keratinocytes and occurs in two forms: cutaneous andgenital. Transmission it believed to occur through direct contact and/orsexual activity. Both cutaneous and genital HPV infection, can result inwarts and latent infections and sometimes recurring infections, whichare controlled by host immunity which controls the symptoms and blocksthe appearance of warts, but leaves the host capable of transmitting theinfection to others.

Infection with HPV can also lead to certain cancers, such as cervical,anal, vulvar, penile and oropharynial cancer. There are no known curesfor HPV infection, but current treatment is topical application ofImiquimod, which stimulates the immune system to attack the affectedarea. The clearance of HPV latent infections would be of great clinicalbenefit. The anti-LAG-3 antibody molecule (alone or in combination withan anti-PD-1, anti-PD-L1 or anti-TIM-3 antibody molecule) may becombined with conventional treatments for HPV infections for therapeuticadvantage.

Bacterial Infections

Some examples of pathogenic bacteria causing infections treatable bymethods of the invention include syphilis, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lymes disease bacteria. Theanti-LAG-3 antibody molecule (alone or in combination with an anti-PD-1,anti-PD-L1 or anti-TIM-3 antibody molecule) can be used in combinationwith existing treatment modalities for the aforesaid infections. Forexample, Treatments for syphilis include penicillin (e.g., penicillinG.), tetracycline, doxycycline, ceftriaxone and azithromycin.

Lyme disease, caused by Borrelia burgdorferi is transmitted into humansthrough tick bites. The disease manifests initially as a localized rash,followed by flu-like symptoms including malaise, fever, headache, stiffneck and arthralgias. Later manifestations can include migratory andpolyarticular arthritis, neurologic and cardiac involvement with cranialnerve palsies and radiculopathy, myocarditis and arrhythmias. Some casesof Lyme disease become persistent, resulting in irreversible damageanalogous to tertiary syphilis. Current therapy for Lyme diseaseincludes primarily the administration of antibiotics.Antibiotic-resistant strains may be treated with hydroxychloroquine ormethotrexate. Antibiotic refractory patients with neuropathic pain canbe treated with gabapentin. Minocycline may be helpful in late/chronicLyme disease with neurological or other inflammatory manifestations.

Other forms of borreliosis, such as those resulting from B. recurentis,B. hermsii, B. turicatae, B. parikeri., B. hispanica, B. duttonii and B.persica, as well leptospirosis (E.g., L. interrogans), typically resolvespontaneously unless blood titers reach concentrations to causeintrahepatic obstruction.

Fungi and Parasites

Some examples of pathogenic fungi causing infections treatable bymethods of the invention include Candida (albicans, krusei, glabrata,tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus,niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrixschenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis,Coccidioides immitis and Histoplasma capsulatum.

Some examples of pathogenic parasites causing infections treatable bymethods of the invention include Entamoeba histolytica, Balantidiumcoli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

Additional Combination Therapies

Combinations of anti-LAG-3 antibody molecules with one or more secondtherapeutics are provided herein. Many of the combinations in thissection are useful in treating cancer, but other indications are alsodescribed. This section focuses on combinations of anti-LAG-3 antibodymolecules, optionally in combination with one or more immunomodulators(e.g., an anti-PD-1 antibody molecule, an anti-TIM-3 antibody molecule,or an anti-PD-L antibody molecule), with one or more of the agentsdescribed in Table 7. In the combinations herein below, in oneembodiment, the anti-LAG-3 antibody molecule comprises (i) a heavy chainvariable region (VH) comprising a VHCDR1 amino acid sequence chosen fromSEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 286; a VHCDR2 amino acidsequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO:3; and (ii) a light chain variable region (VL) comprising a VLCDR aminoacid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ IDNO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12.

In one embodiment, the anti-LAG-3 antibody molecule, e.g., an anti-LAG-3antibody molecule as described herein, alone or in combination with oneor more other immunomodulators, is used in combination with a PKCinhibitor, Sotrastaurin (Compound A1), or a compound disclosed in PCTPublication No. WO 2005/039549, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the PKC inhibitor is Sotrastaurin(Compound A1) or a compound disclosed in PCT Publication No. WO2005/039549. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with Sotrastaurin (Compound A1), or a compound asdescribed in PCT Publication No. WO 2005/039549, to treat a disordersuch as a cancer, a melanoma, a non-Hodgkin lymphoma, an inflammatorybowel disease, transplant rejection, an ophthalmic disorder, orpsoriasis.

In certain embodiments, Sotrastaurin (Compound A1) is administered at adose of about 20 to 600 mg, e.g., about 200 to about 600 mg, about 50 mgto about 450 mg, about 100 mg to 400 mg, about 150 mg to 350 mg, orabout 200 mg to 300 mg, e.g., about 50 mg, 100 mg, 150 mg, 200 mg, 300mg, 400 mg, 500 mg, or 600 mg. The dosing schedule can vary from e.g.,every other day to daily, twice or three times a day.

In one embodiment, the anti-LAG-3 antibody molecule, e.g., an anti-LAG-3antibody molecule as described herein, alone or in combination with oneor more other immunomodulators, is used in combination with a BCR-ABLinhibitor, TASIGNA (Compound A2, or a compound disclosed in PCTPublication No. WO 2004/005281, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the BCR-ABL inhibitor is TASIGNA,or a compound disclosed in PCT Publication No. WO 2004/005281. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination withTASIGNA (Compound A2), or a compound as described in PCT Publication No.WO 2004/005281, to treat a disorder such as a lymphocytic leukemia,Parkinson's Disease, a neurologic cancer, a melanoma, adigestive/gastrointestinal cancer, a colorectal cancer, a myeloidleukemia, a head and neck cancer, or pulmonary hypertension.

In one embodiment, the BCR-ABL inhibitor or TASIGNA is administered at adose of about 300 mg (e.g., twice daily, e.g., for newly diagnosed Ph+CML-CP), or about 400 mg, e.g., twice daily, e.g., for resistant orintolerant Ph+ CML-CP and CML-AP). BCR-ABL inhibitor or a Compound A2 isadministered at a dose of about 300-400 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an HSP90 inhibitor, such as5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound disclosed in PCT Publication No. WO2010/060937 or WO 2004/072051, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the HSP90 inhibitor is5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound disclosed in PCT Publication No. WO2010/060937 or WO 2004/072051. In one embodiment, an anti-LAG-3 antibodymolecule is used in combination with5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound as described in PCT Publication No. WO2010/060937 or WO 2004/072051, to treat a disorder such as a cancer, amultiple myeloma, a non-small cell lung cancer, a lymphoma, a gastriccancer, a breast cancer, a digestive/gastrointestinal cancer, apancreatic cancer, a colorectal cancer, a solid tumor, or ahematopoiesis disorder.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an inhibitor of PI3K and/or mTOR, Dactolisib (CompoundA4) or8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound disclosed in PCT Publication No. WO2006/122806, to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PI3K and/or mTOR inhibitor is Dactolisib (CompoundA4),8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound disclosed in PCT Publication No. WO2006/122806. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with Dactolisib (Compound A4),8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound described in PCT Publication No. WO2006/122806, to treat a disorder such as a cancer, a prostate cancer, aleukemia (e.g., lymphocytic leukemia), a breast cancer, a brain cancer,a bladder cancer, a pancreatic cancer, a renal cancer, a solid tumor, ora liver cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an FGFR inhibitor,3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) or a compound disclosed in U.S. Pat. No. 8,552,002, totreat a disorder, e.g., a disorder described herein. In one embodiment,the FGFR inhibitor is3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) or a compound disclosed in U.S. Pat. No. 8,552,002. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination withCompound A5, or a compound as described in U.S. Pat. No. 8,552,002, totreat a disorder such as a digestive/gastrointestinal cancer, ahematological cancer, or a solid tumor.

In one embodiment, the FGFR inhibitor or3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) is administered at a dose of about 100-125 mg (e.g., perday), e.g., about 100 mg or about 125 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a PI3K inhibitor, Buparlisib (Compound A6), or acompound disclosed in PCT Publication No. WO 2007/084786, to treat adisorder, e.g., a disorder described herein. In one embodiment, the PI3Kinhibitor is Buparlisib (Compound A6) or a compound disclosed in PCTPublication No. WO 2007/084786. In one embodiment, an anti-LAG-3antibody molecule is used in combination with Buparlisib (Compound A6),or a compound disclosed in PCT Publication No. WO 2007/084786, to treata disorder such as, a prostate cancer, a non-small cell lung cancer, anendocrine cancer, a leukemia, an ovarian cancer, a melanoma, a bladdercancer, a breast cancer, a female reproductive system cancer, adigestive/gastrointestinal cancer, a colorectal cancer, a glioblastomamultiforme, a solid tumor, a non-Hodgkin lymphoma, a hematopoiesisdisorder, or a head and neck cancer.

In one embodiment, the PI3K inhibitor or Buparlisib (Compound A6) isadministered at a dose of about 100 mg (e.g., per day).

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an FGFR inhibitor,8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) or a compound disclosed in PCT Publication No. WO2009/141386 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the FGFR inhibitor is8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) or a compound disclosed in a PCT Publication No. WO2009/141386. In one embodiment, the FGFR inhibitor is8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7). In one embodiment, an anti-LAG-3 antibody molecule isused in combination with8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7), or a compound disclosed in PCT Publication No. WO2009/141386, to treat a disorder such as a cancer characterized byangiogenesis.

In one embodiment, the FGFR inhibitor or8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) is administered at a dose of e.g., from approximately 3 mgto approximately 5 g, more preferably from approximately 10 mg toapproximately 1.5 g per person per day, optionally divided into 1 to 3single doses which may, for example, be of the same size.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a PI3K inhibitor,(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) or a compound disclosed PCT Publication No. WO 2010/029082to treat a disorder, e.g., a disorder described herein. In oneembodiment, the PI3K inhibitor is (S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) or a compound disclosed PCT Publication No. WO2010/029082. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8), or a compound disclosed PCT Publication No. WO2010/029082, to treat a disorder such as a gastric cancer, a breastcancer, a pancreatic cancer, a digestive/gastrointestinal cancer, asolid tumor, and a head and neck cancer.

In one embodiment, the PI3K inhibitor or(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) is administered at a dose of about 150-300, 200-300,200-400, or 300-400 mg (e.g., per day), e.g., about 200, 300, or 400 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an inhibitor of cytochrome P450 (e.g., a CYP17inhibitor) or a compound disclosed in PCT Publication No. WO2010/149755, to treat a disorder, e.g., a disorder described herein. Inone embodiment, the cytochrome P450 inhibitor (e.g., the CYP17inhibitor) is a compound disclosed in PCT Publication No. WO2010/149755. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with a compound disclosed in PCT Publication No. WO2010/149755, to treat prostate cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an HDM2 inhibitor,(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) or a compound disclosed in PCT Publication No. WO2011/076786 to treat a disorder, e.g., a disorder described herein). Inone embodiment, the HDM2 inhibitor is(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) or a compound disclosed in PCT Publication No. WO2011/076786. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10), or a compound disclosed in PCT Publication No. WO2011/076786, to treat a disorder such as a solid tumor.

In one embodiment, the HDM2 inhibitor or(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) is administered at a dose of about 400 to 700 mg, e.g.,administered three times weekly, 2 weeks on and one week off. In someembodiments, the dose is about 400, 500, 600, or 700 mg; about 400-500,500-600, or 600-700 mg, e.g., administered three times weekly.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an iron chelating agent, Deferasirox (also known asEXJADE; Compound A11), or a compound disclosed in PCT Publication No. WO1997/049395 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the iron chelating agent is Deferasirox or a compounddisclosed in PCT Publication No. WO 1997/049395. In one embodiment, theiron chelating agent is Deferasirox (Compound A11). In one embodiment,an anti-LAG-3 antibody molecule is used in combination with Deferasirox(Compound A11), or a compound disclosed in PCT Publication No. WO1997/049395, to treat iron overload, hemochromatosis, or myelodysplasia.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an aromatase inhibitor, Letrozole (also known asFEMARA; Compound A12), or a compound disclosed in U.S. Pat. No.4,978,672 to treat a disorder, e.g., a disorder described herein. In oneembodiment, the aromatase inhibitor is Letrozole (Compound A12) or acompound disclosed in U.S. Pat. No. 4,978,672. In one embodiment, anLAG-3 antibody molecule is used in combination with Letrozole (CompoundA12), or a compound disclosed in U.S. Pat. No. 4,978,672, to treat adisorder such as a cancer, a leiomyosarcoma, an endometrium cancer, abreast cancer, a female reproductive system cancer, or a hormonedeficiency.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a PI3K inhibitor, e.g., a pan-PI3K inhibitor,(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13) or a compound disclosed in PCT Publication No.WO2013/124826 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PI3K inhibitor is(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13) or a compound disclosed in PCT Publication No.WO2013/124826. In one embodiment, an anti-LAG-3 antibody molecule isused in combination with(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13), or a compound disclosed in PCT Publication No.WO2013/124826, to treat a disorder such as a cancer or an advanced solidtumor.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an inhibitor of p53 and/or a p53/Mdm2 interaction,(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14), or a compound disclosed in PCT Publication No.WO2013/111105 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the p53 and/or a p53/Mdm2 interaction inhibitor is(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14) or a compound disclosed in PCT Publication No.WO2013/111105. In one embodiment, an anti-LAG-3 antibody molecule isused in combination with(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14), or a compound disclosed in PCT Publication No.WO2013/111105, to treat a disorder such as a cancer or a soft tissuesarcoma.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a CSF-1R tyrosine kinase inhibitor,4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15), or a compound disclosed in PCT Publication No. WO2005/073224 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the CSF-1R tyrosine kinase inhibitor is4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15) or a compound disclosed in PCT Publication No. WO2005/073224. In one embodiment, a LAG-3 antibody molecule is used incombination with4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15) or a compound disclosed in PCT Publication No. WO2005/073224, to treat a disorder such as cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an apoptosis inducer and/or an angiogenesis inhibitor,such as Imatinib mesylate (also known as GLEEVEC; Compound A16) or acompound disclosed in PCT Publication No. WO1999/003854 to treat adisorder, e.g., a disorder described. In one embodiment, the apoptosisinducer and/or an angiogenesis inhibitor is Imatinib mesylate (CompoundA16) or a compound disclosed in PCT Publication No. WO1999/003854. Inone embodiment, an anti-LAG-3 antibody molecule is used in combinationwith Imatinib mesylate (Compound A16), or a compound disclosed in PCTPublication No. WO1999/003854, to treat a disorder such as a cancer, amultiple myeloma, a prostate cancer, a non-small cell lung cancer, alymphoma, a gastric cancer, a melanoma, a breast cancer, a pancreaticcancer, a digestive/gastrointestinal cancer, a colorectal cancer, aglioblastoma multiforme, a liver cancer, a head and neck cancer, asthma,multiple sclerosis, allergy, Alzheimer's dementia, amyotrophic lateralsclerosis, or rheumatoid arthritis.

In certain embodiments, Imatinib mesylate (Compound A16) is administeredat a dose of about 100 to 1000 mg, e.g., about 200 mg to 800 mg, about300 mg to 700 mg, or about 400 mg to 600 mg, e.g., about 200 mg, 300 mg,400 mg, 500 mg, 600 mg, or 700 mg. The dosing schedule can vary frome.g., every other day to daily, twice or three times a day. In oneembodiment, Imatinib mesylate is administered at an oral dose from about100 mg to 600 mg daily, e.g., about 100 mg, 200 mg, 260 mg, 300 mg, 400mg, or 600 mg daily.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a JAK inhibitor,2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514, to treat a disorder,e.g., a disorder described herein. In one embodiment, the JAK inhibitoris2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514. In one embodiment, anLAG-3 antibody molecule is used in combination with2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514, to treat a disordersuch as colorectal cancer, myeloid leukemia, hematological cancer,autoimmune disease, non-Hodgkin lymphoma, or thrombocythemia.

In one embodiment, the JAK inhibitor or a2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof is administered at adose of about 400-600 mg (e.g., per day), e.g., about 400, 500, or 600mg, or about 400-500 or 500-600 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a JAK inhibitor, Ruxolitinib Phosphate (also known asJAKAFI; Compound A18) or a compound disclosed in PCT Publication No. WO2007/070514 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the JAK inhibitor is Ruxolitinib Phosphate (CompoundA18) or a compound disclosed in PCT Publication No. WO 2007/070514. Inone embodiment, an anti-LAG-3 antibody molecule is used in combinationwith Ruxolitinib Phosphate (Compound A18), or a compound disclosed inPCT Publication No. WO 2007/070514, to treat a disorder such as aprostate cancer, a lymphocytic leukemia, a multiple myeloma, a lymphoma,a lung cancer, a leukemia, cachexia, a breast cancer, a pancreaticcancer, rheumatoid arthritis, psoriasis, a colorectal cancer, a myeloidleukemia, a hematological cancer, an autoimmune disease, a non-Hodgkinlymphoma, or thrombocythemia.

In one embodiment, the JAK inhibitor or Ruxolitinib Phosphate (CompoundA18) is administered at a dose of about 15-25 mg, e.g., twice daily. Insome embodiments, the dose is about 15, 20, or 25 mg, or about 15-20 or20-25 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a deacetylase (DAC) inhibitor, Panobinostat (CompoundA19), or a compound disclosed in PCT Publication No. WO 2014/072493 totreat a disorder, e.g., a disorder described herein. In one embodiment,the DAC inhibitor is Panobinostat (Compound A19) or a compound disclosedin PCT Publication No. WO 2014/072493. In one embodiment, an anti-LAG-3antibody molecule is used in combination with Panobinostat (CompoundA19), a compound disclosed in PCT Publication No. WO 2014/072493, totreat a disorder such as a small cell lung cancer, arespiratory/thoracic cancer, a prostate cancer, a multiple myeloma,myelodysplastic syndrome, a bone cancer, a non-small cell lung cancer,an endocrine cancer, a lymphoma, a neurologic cancer, a leukemia,HIV/AIDS, an immune disorder, transplant rejection, a gastric cancer, amelanoma, a breast cancer, a pancreatic cancer, a colorectal cancer, aglioblastoma multiforme, a myeloid leukemia, a hematological cancer, arenal cancer, a non-Hodgkin lymphoma, a head and neck cancer, ahematopoiesis disorders, or a liver cancer.

In one embodiment, the DAC inhibitor or Panobinostat (Compound A19) isadministered at a dose of about 20 mg (e.g., per day).

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an inhibitor of one or more of cytochrome P450 (e.g.,11B2), aldosterone or angiogenesis, Osilodrostat (Compound A20), or acompound disclosed in PCT Publication No. WO2007/024945 to treat adisorder, e.g., a disorder described herein. In one embodiment, theinhibitor of one or more of cytochrome P450 (e.g., 11B2), aldosterone orangiogenesis is Osilodrostat (Compound A20) or a compound disclosed inPCT Publication No. WO2007/024945. In one embodiment, an anti-LAG-3antibody molecule is used in combination with Osilodrostat (CompoundA20), or a compound disclosed in PCT Publication No. WO2007/024945, totreat a disorder such as Cushing's syndrome, hypertension, or heartfailure therapy.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a IAP inhibitor,(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003 totreat a disorder, e.g., a disorder described herein. In one embodiment,the IAP inhibitor is(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003. Inone embodiment, an anti-LAG-3 antibody molecule is used in combinationwith(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21), or a compound disclosed in U.S. Pat. No. 8,552,003, totreat a disorder such as a multiple myeloma, a breast cancer, an ovariancancer, a pancreatic cancer, or a hematopoiesis disorder.

In one embodiment, the IAP inhibitor or(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003 isadministered at a dose of approximately 1800 mg, e.g., once weekly.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a Smoothened (SMO) inhibitor, Sonidegib phosphate (CompoundA22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the SMO inhibitor is Sonidegibphosphate (Compound A22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120. In one embodiment, an anti-LAG-3 antibodymolecule is used in combination with Sonidegib phosphate (Compound A22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120 to treat a disorder such as a cancer, amedulloblastoma, a small cell lung cancer, a prostate cancer, a basalcell carcinoma, a pancreatic cancer, or an inflammation.

In certain embodiments, Sonidegib phosphate (Compound A22) isadministered at a dose of about 20 to 500 mg, e.g., about 40 mg to 400mg, about 50 mg to 300 mg, or about 100 mg to 200 mg, e.g., about 50 mg,100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. The dosing schedule can varyfrom e.g., every other day to daily, twice or three times a day.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an Alk inhibitor, ceritinib (also known as ZYKADIA;Compound A23) or a compound disclosed in PCT Publication No. WO2007/131201 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the Alk inhibitor is ceritinib (Compound A23) or acompound disclosed in PCT Publication No. WO 2007/131201. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination withceritinib (Compound A23), or a compound disclosed in PCT Publication No.WO 2007/131201, to treat a disorder such as non-small cell lung canceror solid tumors.

In one embodiment, the Alk inhibitor or ceritinib (Compound A23) isadministered at a dose of approximately 750 mg, e.g., once daily.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a JAK and/or CDK4/6 inhibitor,7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24), or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980 to treat a disorder, e.g., a disorder describedherein. In one embodiment, the JAK and/or CDK4/6 inhibitor is7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24) or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980. In one embodiment, an anti-LAG-3 antibodymolecule is used in combination with7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24), or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980, to treat a disorder such as a lymphoma, aneurologic cancer, a melanoma, a breast cancer, or a solid tumor.

In one embodiment, the JAK and/or CDK4/6 inhibitor or7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24) is administered at a dose of approximately 200-600 mg,e.g., per day. In one embodiment, the compound is administered at a doseof about 200, 300, 400, 500, or 600 mg, or about 200-300, 300-400,400-500, or 500-600 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a prolactin receptor (PRLR) inhibitor, a human monoclonalantibody molecule (Compound A26) as disclosed in U.S. Pat. No.7,867,493), to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PRLR inhibitor is a human monoclonal antibody(Compound A26) disclosed in U.S. Pat. No. 7,867,493. In one embodiment,an anti-LAG-3 antibody molecule is used in combination with humanmonoclonal antibody molecule (Compound A26) described in U.S. Pat. No.7,867,493 to treat a disorder such as, a cancer, a prostate cancer, or abreast cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a PIM Kinase inhibitor,N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27) or a compound disclosed in PCT Publication No. WO2010/026124 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PIM Kinase inhibitor isN-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27) or a compound disclosed in PCT Publication No. WO2010/026124. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination withN-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27), or a compound disclosed in PCT Publication No. WO2010/026124, to treat a disorder such as a multiple myeloma,myelodysplastic syndrome, a myeloid leukemia, or a non-Hodgkin lymphoma.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a Wnt signaling inhibitor,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) or a compound disclosed in PCT publication No. WO2010/101849 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the Wnt signaling inhibitor is2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) or a compound disclosed in PCT publication No. WO2010/101849. In one embodiment, the Wnt signaling inhibitor is2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28). In one embodiment, an anti-LAG-3 antibody molecule isused in combination with2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28), or a compound disclosed in PCT publication No. WO2010/101849, to treat a disorder such as a solid tumor (e.g., a head andneck cancer, a squamous cell carcinoma, a breast cancer, a pancreaticcancer, or a colon cancer).

In certain embodiments,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) is administered at a dose of about 1 to 50 mg, e.g.,about 2 mg to 45 mg, about 3 mg to 40 mg, about 5 mg to 35 mg, 5 mg to10 mg, or about 10 mg to 30 mg, e.g., about 2 mg, 5 mg, 10 mg, 20 mg, 30mg, or 40 mg. The dosing schedule can vary from e.g., every other day todaily, twice or three times a day.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a BRAF inhibitor, Encorafenib (Compound A29), or acompound disclosed in PCT Publication No. WO 2011/025927 to treat adisorder, e.g., a disorder described herein. In one embodiment, the BRAFinhibitor is Encorafenib (Compound A29) or a compound disclosed in PCTPublication No. WO 2011/025927. In one embodiment, an anti-LAG-3antibody molecule is used in combination with Encorafenib (CompoundA29), or a compound disclosed in PCT Publication No. WO 2011/025927, totreat a disorder such as a non-small cell lung cancer, a melanoma, or acolorectal cancer.

In one embodiment, the BRAF inhibitor or Encorafenib (Compound A29) isadministered at a dose of about 200-300, 200-400, or 300-400 mg, e.g.,per day. In one embodiment, the compound is administered at a dose ofabout 200, about 300 or about 400 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a CDK4/6 inhibitor,7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30), or a compound disclosed in PCT publication No. WO2011/101409 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the CDK4/6 inhibitor is7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30) or a compound disclosed in PCT publication No. WO2011/101409. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30), or a compound disclosed in PCT publication No. WO2011/101409, to treat a disorder such as a cancer, a mantle celllymphoma, a liposarcoma, a non-small cell lung cancer, a melanoma, asquamous cell esophageal cancer, or a breast cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a HER3 inhibitor, Compound A31, or a compound disclosedin PCT Publication No. WO 2012/022814, to treat a disorder, e.g., adisorder described herein. In one embodiment, the HER3 inhibitor isCompound A31 or a compound disclosed in PCT Publication WO 2012/022814.In one embodiment, an anti-LAG-3 antibody molecule is used incombination with Compound A31, or a compound disclosed in PCTPublication WO 2012/022814, to treat a disorder such as a gastriccancer, an esophageal cancer, a head and neck cancer, a squamous cellcarcinoma, a stomach cancer, a breast cancer (e.g., metastatic breastcancer), or a digestive/gastrointestinal cancer.

In some embodiments, Compound A31 is a human monoclonal antibodymolecule.

In one embodiment, the HER3 inhibitor or Compound A31 is administered ata dose of about 3, 10, 20, or 40 mg/kg, e.g., once weekly (QW). In oneembodiment, the compound is administered at a dose of about 3-10, 10-20,or 20-40 mg/kg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an FGFR2 and/or FGFR4 inhibitor, Compound A32, or a compounddisclosed in a publication PCT Publication No. WO 2014/160160 (e.g., anantibody molecule drug conjugate against an FGFR2 and/or FGFR4, e.g.,mAb 12425), to treat a disorder, e.g., a disorder described herein. Inone embodiment, the FGFR2 and/or FGFR4 inhibitor is Compound A32 or acompound disclosed in a publication PCT Publication No. WO 2014/160160.In one embodiment, an anti-LAG-3 antibody molecule is used incombination with Compound A32, or a compound as described in Table 7, totreat a disorder such as a cancer, a gastric cancer, a breast cancer, arhabdomyosarcoma, a liver cancer, an adrenal cancer, a lung cancer, anesophageal cancer, a colon cancer, or an endometrial cancer.

In some embodiments, Compound A32 is an antibody molecule drug conjugateagainst an FGFR2 and/or FGFR4, e.g., mAb 12425.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an M-CSF inhibitor, Compound A33, or a compound disclosed inPCT Publication No. WO 2004/045532 (e.g., an antibody molecule or Fabfragment against M-CSF), to treat a disorder, e.g., a disorder describedherein. In one embodiment, the M-CSF inhibitor is Compound A33 or acompound disclosed in PCT Publication No. WO 2004/045532. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination withCompound A33, or a compound as described in PCT Publication No. WO2004/045532, to treat a disorder such as a cancer, a prostate cancer, abreast cancer, or pigmented villonodular synovitis (PVNS).

In embodiments, Compound A33 is a monoclonal antibody molecule againstM-CSF or a fragment (e.g., Fab fragment) thereof. In embodiments, theM-CSF inhibitor or Compound A33 is administered at an average dose ofabout 10 mg/kg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a MEK inhibitor, Binimetinib (Compound A34), or acompound disclosed in PCT Publication No. WO 2003/077914 to treat adisorder, e.g., a disorder described herein. In one embodiment, the MEKinhibitor is Binimetinib (Compound A34), or a compound disclosed in PCTPublication No. WO 2003/077914. In one embodiment, an anti-LAG-3antibody molecule is used in combination with Binimetinib (CompoundA34), or a compound disclosed in PCT Publication No. WO 2003/077914, totreat a disorder such as a non-small cell lung cancer, a multisystemgenetic disorder, a melanoma, an ovarian cancer, adigestive/gastrointestinal cancer, a rheumatoid arthritis, or acolorectal cancer.

In one embodiment, the MEK inhibitor or Binimetinib (Compound A34) isadministered at a dose of about 45 mg, e.g., twice daily.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an inhibitor of one or more of c-KIT, histamine release,Flt3 (e.g., FLK2/STK1) or PKC, Midostaurin (Compound A35) or a compounddisclosed in PCT Publication No. WO 2003/037347 to treat a disorder,e.g., a disorder described herein. In one embodiment, the inhibitor isMidostaurin (Compound A35) or compound disclosed in PCT Publication No.WO 2003/037347. In one embodiment, the inhibitor of one or more ofc-KIT, histamine release, Flt3 (e.g., FLK2/STK1) or PKC is Midostaurin.In one embodiment, an anti-LAG-3 antibody molecule is used incombination with Midostaurin (Compound A35), or compound disclosed inPCT Publication No. WO 2003/037347, to treat a disorder such as acancer, a colorectal cancer, a myeloid leukemia, myelodysplasticsyndrome, an age-related macular degeneration, a diabetic complication,or a dermatologic disorder.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a TOR inhibitor (e.g., mTOR inhibitor), Everolimus(also known as AFINITOR; Compound A36) or a Compound disclosed in PCTPublication No. WO 2014/085318 to treat a disorder, e.g., a disorderdescribed herein). In one embodiment, the TOR inhibitor is Everolimus(Compound A36) or a Compound disclosed in PCT Publication No. WO2014/085318. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with Everolimus (Compound A36) to treat a disorder suchas an interstitial lung disease, a small cell lung cancer, arespiratory/thoracic cancer, a prostate cancer, a multiple myeloma, asarcoma, an age-related macular degeneration, a bone cancer, tuberoussclerosis, a non-small cell lung cancer, an endocrine cancer, alymphoma, a neurologic disorders, an astrocytoma, a cervical cancer, aneurologic cancer, a leukemia, an immune disorders, transplantrejection, a gastric cancer, a melanoma, epilepsy, a breast cancer, or abladder cancer.

In one embodiment, the TOR inhibitor or Everolimusis (Compound A36)administered at a dose of about 2.5-20 mg/day. In one embodiment, thecompound is administered at a dose of about 2.5, 5, 10, or 20 mg/day,e.g., about 2.5-5, 5-10, or 10-20 mg/day.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an inhibitor of one or more of VEGFR-2, PDGFRbeta, KIT orRaf kinase C,1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37) or a compound disclosed in PCT Publication No. WO2007/030377 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the inhibitor of one or more of VEGFR-2, PDGFRbeta, KITor Raf kinase C is1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37) or a compound disclosed in PCT Publication No. WO2007/030377. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37), or a compound disclosed in PCT Publication No. WO2007/030377, to treat a disorder such as a cancer, a melanoma, or asolid tumor.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a somatostatin agonist and/or growth hormone releaseinhibitor, Pasireotide diaspartate (also known as SIGNIFOR; CompoundA38) or a compound disclosed in PCT Publication No. WO2002/010192 orU.S. Pat. No. 7,473,761 to treat a disorder, e.g., a disorder describedherein. In one embodiment, the somatostatin agonist and/or growthhormone release inhibitor is Pasireotide diaspartate (Compound A38) or acompound disclosed in PCT Publication No. WO2002/010192 or U.S. Pat. No.7,473,761. In one embodiment, an anti-LAG-3 antibody molecule is used incombination with Pasireotide diaspartate (Compound A38), or a compounddisclosed in PCT Publication No. WO2002/010192 or U.S. Pat. No.7,473,761, to treat a disorder such as a prostate cancer, an endocrinecancer, a neurologic cancer, a skin cancer (e.g., a melanoma), apancreatic cancer, a liver cancer, Cushing's syndrome, agastrointestinal disorder, acromegaly, a liver and biliary tractdisorder, or liver cirrhosis.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a signal transduction modulator and/or angiogenesisinhibitor, Dovitinib (Compound A39) or a compound disclosed in PCTPublication No. WO 2009/115562 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the signal transduction modulatorand/or angiogenesis inhibitor is Dovitinib (Compound A39) or a compounddisclosed in PCT Publication No. WO 2009/115562. In one embodiment, ananti-LAG-3 antibody molecule is used in combination with Dovitinib(Compound A39), or a compound disclosed in PCT Publication No. WO2009/115562, to treat a disorder such as a cancer, arespiratory/thoracic cancer, a multiple myeloma, a prostate cancer, anon-small cell lung cancer, an endocrine cancer, or a neurologicalgenetic disorder.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an EGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the EGFR inhibitor is(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757, to treat a disorder such as a cancer, e.g., a solid tumor.

In one embodiment, the EGFR inhibitor or(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) is administered at a dose of 150-250 mg, e.g., per day.In one embodiment, the compound is administered at a dose of about 150,200, or 250 mg, or about 150-200 or 200-250 mg.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an ALK inhibitor,N⁶-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42) or a compound disclosed in PCT Publication No. WO2008/073687 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the ALK inhibitor isN⁶-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42) or a compound disclosed in PCT Publication No. WO2008/073687. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination withN6-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42), or a compound disclosed in PCT Publication No. WO2008/073687, to treat a disorder such as a cancer, an anaplasticlarge-cell lymphoma (ALCL), a non-small cell lung carcinoma (NSCLC), ora neuroblastoma.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination an IGF-1R inhibitor,3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44), or5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45) or a compound disclosed in PCT Publication No. WO2010/002655 to treat a disorder, e.g., a disorder described. In oneembodiment, the IGF-1R inhibitor is3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44),5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45), or a compound disclosed in PCT Publication No. WO2010/002655. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44),5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45), or a compound disclosed in PCT Publication No. WO2010/002655, to treat a disorder such as a cancer or a sarcoma.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination a P-Glycoprotein 1 inhibitor, Valspodar (also known asAMDRAY; Compound A46) or a compound disclosed in EP 296122 to treat adisorder, e.g., a disorder described herein. In one embodiment, theP-Glycoprotein 1 inhibitor is Valspodar (Compound A46) or a compounddisclosed in EP 296122. In one embodiment, an anti-LAG-3 antibodymolecule is used in combination with Valspodar (Compound A46), or acompound disclosed in EP 296122, to treat a disorder such as a cancer ora drug-resistant tumor.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination one or more of a VEGFR inhibitor, Vatalanib succinate(Compound A47) or a compound disclosed in EP 296122 to treat a disorder,e.g., a disorder described herein. In one embodiment, the VEGFRinhibitor is Vatalanib succinate (Compound A47) or a compound disclosedin EP 296122. In one embodiment, an anti-LAG-3 antibody molecule is usedin combination with Vatalanib succinate (Compound A47), or a compounddisclosed in EP 296122, to treat cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an IDH inhibitor or a compound disclosed inWO2014/141104 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the IDH inhibitor is a compound disclosed in PCTPublication No. WO2014/141104. In one embodiment, an anti-LAG-3 antibodymolecule is used in combination with a compound disclosed inWO2014/141104 to treat a disorder such as a cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a BCL-ABL inhibitor or a compound disclosed in PCTPublication No. WO2013/171639, WO2013/171640, WO2013/171641, orWO2013/171642 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the BCL-ABL inhibitor is a compound disclosed in PCTPublication No. WO2013/171639, WO2013/171640, WO2013/171641, orWO2013/171642. In one embodiment, an anti-LAG-3 antibody molecule isused in combination with a compound disclosed in PCT Publication No.WO2013/171639, WO2013/171640, WO2013/171641, or WO2013/171642 to treat adisorder such as a cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a c-RAF inhibitor or a compound disclosed in PCTPublication No. WO2014/151616 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the c-RAF inhibitor is Compound A50or a compound disclosed in PCT Publication No. WO2014/151616. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination witha compound disclosed in PCT Publication No. WO2014/151616 to treat adisorder such as a cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with an ERK1/2 ATP competitive inhibitor or a compounddisclosed in International Patent Application No. PCT/US2014/062913 totreat a disorder, e.g., a disorder described herein. In one embodiment,the ERK1/2 ATP competitive inhibitor is a compound disclosed inInternational Patent Application No. PCT/US2014/062913. In oneembodiment, an anti-LAG-3 antibody molecule is used in combination withCompound A51 or a compound disclosed in International Patent ApplicationNo. PCT/US2014/062913 to treat a disorder such as a cancer.

In another embodiment, the anti-LAG-3 antibody molecule, e.g., ananti-LAG-3 antibody molecule as described herein, alone or incombination with one or more other immunomodulators, is used incombination with a tyrosine kinase inhibitor, (Compound A52) or acompound disclosed in PCT Publication No. WO2005/073224 to treat adisorder, e.g., a disorder described herein. In one embodiment, thetyrosine kinase inhibitor is4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A52) or a compound disclosed in PCT Publication No.WO2005/073224. In one embodiment, an anti-LAG-3 antibody molecule isused in combination with4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A52), or a compound disclosed in PCT Publication No.WO2005/073224, to treat a disorder such as a cancer.

In some embodiments, the anti-LAG-3 antibody molecule is administered incombination with one or more agents selected from, Compound A8, CompoundA17, Compound A23, Compound A24, Compound A27, Compound A29, andCompound A33.

In some embodiments, an anti-LAG-3 antibody molecule is administered incombination with an anti-cancer agent having a known activity in animmune cell assay, e.g., in one or more of a huMLR assay, a T cellproliferation assay, and a B-cell proliferation assay. Exemplary assaysare described below. Based on the assay, an IC50 for can be calculatedfor each test agent. In embodiments, the anti-cancer agent has an IC50of, e.g., 0-1 μM, 1-4 μM, or greater than 4 μM, e.g., 4-10 μM or 4-20μM. In embodiments, the second therapeutic agent is chosen from one ormore of: Compound A9, Compound A16, Compound A17, Compound A21, CompoundA22, Compound A25, Compound A28, Compound A48, and Compound 49.

In some embodiments, the Compound A28 (or a compound related to CompoundA28) is administered at a dose of approximately 5-10 or 10-30 mg. Insome embodiments, the Compound A22 (or compound related to Compound A22)is administered at a dose of about 200 mg. In some embodiments, theCompound A17 (or compound related to Compound A17) is administered at adose of approximately 400-600 mg. In some embodiments, the Compound A16(or compound related to Compound A16) is administered at a dose ofapproximately 400-600 mg PO qDay. In some embodiments, the Compound A29(or compound related to Compound A29) is administered at a dose ofapproximately 200-400 or 300-400 mg. In some embodiments, the CompoundA24 (or compound related to Compound A24) is administered at a dose ofapproximately 200-600 mg. In some embodiments, the Compound A23(ceritinib) (or compound related to ceritinib) is administered at a doseof approximately 750 mg once daily. In some embodiments, the Compound A8(or compound related to Compound A8) is administered at a dose ofapproximately 200-400 or 300-400 mg. In some embodiments, the CompoundA5 (or compound related to Compound A5) is administered at a dose ofapproximately 100-125 mg. In some embodiments, the Compound A6 (orcompound related to Compound A6) is administered at a dose of about 100mg. In some embodiments, the Compound A1 (or compound related toCompound A1) is administered at a dose of approximately 200-300 or200-600 mg. In some embodiments, the Compound A40 (or compound relatedto Compound A40) is administered at a dose of approximately 150-250 mg.In some embodiments, the Compound A10 (or compound related to CompoundA10) is administered at a dose of approximately 400 to 700 mg, e.g.,administered three times weekly, 2 weeks on and one week off. In someembodiments, the BCR-ABL inhibitor is administered at a dose ofapproximately 20 mg bid-80 mg bid.

Exemplary huMLR assay and B or T cell proliferation assays are providedbelow.

Human Mixed Lymphocyte Reaction

The Mixed Lymphocyte Reaction (MLR) is a functional assay which measuresthe proliferative response of lymphocytes from one individual (theresponder) to lymphocytes from another individual (the stimulator). Toperform an allogeneic MLR, peripheral blood mononuclear cells (PBMC)from three donors were isolated from buffy-coats of unknown HLA type(Kantonspital Blutspendezentrum from Bern and Aarau, Switzerland). Thecells were prepared at 2×10⁵ in 0.2 mL of culture medium containing RPMI1640 GlutaMAX™ with 10% fetal calf serum (FCS), 100U penicillin/100 μgstreptomycin, 50 μM 2-Mercaptoethanol. Individual 2-way reactions wereset up by mixing PBMC from two different donors at a 1:1 ratio andco-cultures were done in triplicates in flat-bottomed 96-well tissueculture plates for 6 days at 37° C., 5% CO2, in presence or not of an8-point concentration range of test compounds. Cells were pulsed with3H-TdR (1 μCi/0.2 mL) for the last 16h of culture and incorporatedradioactivity was used as a measure of cell proliferation. Theconcentration that inhibited 50% of the maximal huMLR response (IC50)was calculated for each compound. Cyclosporine was used as a positivecontrol of huMLR inhibition.

Human B Cell Proliferation Assay

PBMC were freshly isolated by Ficoll-Paque density gradient from humanblood and subjected to negative B-cell isolation. B cells wereresuspended in culture medium (RPMI 1640, HEPES, 10% FCS, 50 μg/mLgentamicine, 50 μM 2-Mercaptoethanol, 1×ITS (Insulin, Transferrin andSodium Selenite), 1× Non-Essential Amino-Acids) at a concentration of9.104 per well in a flat-bottom 96-well culture plate. B cellstimulation was performed by human anti-IgM antibody molecule (30 ug/mL)and IL-4 (75 ng/mL) or by CD40 ligand (3 ug/mL) and IL-4 (75 ng/mL) inpresence or not of a 7-point concentration range of test compounds.After 72h of culture at 37° C., 10% CO2, cells were pulsed with 3H-TdR(1 μCi/well) for the last 6 h of culture.

B cells were then harvested and the incorporation of thymidine wasmeasured using a scintillation counter. Of each duplicate treatment, themean was calculated and these data were plotted in XLfit 4 to determinethe respective IC50 values.

Human T Cell Proliferation Assay

PBMC were freshly isolated by Ficoll-Paque density gradient from humanblood and subjected to negative isolation of T cells. T cells wereprepared in culture medium (RPMI 1640, HEPES, 10% FCS, 50 μg/mLgentamicine, 50 μM 2-Mercaptoethanol, 1×ITS (Insulin, Transferrin andSodium Selenite), 1× Non-Essential Amino-Acids) at a concentration of8.104 per well in a flat-bottom 96-well culture plate. T cellstimulation was performed by human anti-CD3 antibody molecule (10 ug/mL)or by human anti-CD3 antibody molecule (5 μg/mL) and anti-CD28 antibodymolecule (1 μg/mL) in presence or not of a 7-point concentration rangeof test compounds. After 72h of culture at 37° C., 10% CO₂, cells werepulsed with 3H-TdR (1 μCi/well) for the last 6h of culture. Cellproliferation was measured by the incorporation of thymidine allowingIC50 determination for each tested compound.

Decreasing an Immune Response

Anti-LAG-3 antibodies can be used to modulate, e.g., provoke andamplify, an immune response, e.g., an autoimmune response. For example,anti-LAG-3 blockade in conjunction with various self proteins can beused to devise vaccination protocols to efficiently generate immuneresponses against these self proteins for disease treatment. Indeed,many anti-tumor responses involve anti-self reactivities (van Elsas etal. (2001) J. Exp. Med. 194:481-489; Overwijk, et al. (1999) Proc. Natl.Acad. Sci. U.S.A. 96: 2982-2987; Rosenberg & White (1996) J. ImmunotherEmphasis Tumor Immunol 19 (1): 81-4). Further, Alzheimer's diseaseinvolves inappropriate accumulation of AP3 peptide in amyloid depositsin the brain; antibody responses against amyloid are able to clear theseamyloid deposits (Schenk et al., (1999) Nature 400: 173-177).

Other self proteins can also be used as targets such as IgE for thetreatment of allergy and asthma, and TNFc for rheumatoid arthritis.Antibody responses to various hormones can be induced by the use ofanti-LAG-3 antibody. Neutralizing antibody responses to reproductivehormones can be used for contraception. Neutralizing antibody responseto hormones and other soluble factors that are required for the growthof particular tumors can also be considered as candidate vaccinationtargets.

Analogous methods as described above for the use of anti-LAG-3 antibodycan be used for induction of therapeutic autoimmune responses to treatpatients having an inappropriate accumulation of other self-antigens,such as amyloid deposits, including AP3 in Alzheimer's disease,cytokines such as TNFa, and IgE.

In other embodiments, the anti-LAG-3 antibody molecules are administeredto a subject in conjunction with (e.g., before, simultaneously orfollowing) one or more of: bone marrow transplantation, T cell ablativetherapy using chemotherapy agents such as, fludarabine, external-beamradiation therapy (XRT), cyclophosphamide, and/or antibodies such asOKT3 or CAMPATH. In one embodiment, the anti-LAG-3 antibody moleculesare administered following B-cell ablative therapy such as agents thatreact with CD20, e.g., Rituxan. For example, in one embodiment, subjectsmay undergo standard treatment with high dose chemotherapy followed byperipheral blood stem cell transplantation. In certain embodiments,following the transplant, subjects receive the anti-LAG-3 antibodymolecules. In an additional embodiment, the anti-LAG-3 antibodymolecules are administered before or following surgery.

Diagnostic Uses

In one aspect, the present invention provides a diagnostic method fordetecting the presence of a LAG-3 protein in vitro (e.g., in abiological sample, such as a tissue biopsy, e.g., from a canceroustissue) or in vivo (e.g., in vivo imaging in a subject). The methodincludes: (i) contacting the sample with an antibody molecule describedherein, or administering to the subject, the antibody molecule;(optionally) (ii) contacting a reference sample, e.g., a control sample(e.g., a control biological sample, such as plasma, tissue, biopsy) or acontrol subject)); and (iii) detecting formation of a complex betweenthe antibody molecule, and the sample or subject, or the control sampleor subject, wherein a change, e.g., a statistically significant change,in the formation of the complex in the sample or subject relative to thecontrol sample or subject is indicative of the presence of LAG-3 in thesample. The antibody molecule can be directly or indirectly labeled witha detectable substance to facilitate detection of the bound or unboundantibody. Suitable detectable substances include various enzymes,prosthetic groups, fluorescent materials, luminescent materials andradioactive materials, as described above and described in more detailbelow.

The term “sample,” as it refers to samples used for detectingpolypeptides includes, but is not limited to, cells, cell lysates,proteins or membrane extracts of cells, body fluids, or tissue samples.

Complex formation between the antibody molecule and LAG-3 can bedetected by measuring or visualizing either the binding molecule boundto the LAG-3 antigen or unbound binding molecule. Conventional detectionassays can be used, e.g., an enzyme-linked immunosorbent assays (ELISA),a radioimmunoassay (RIA) or tissue immunohistochemistry. Alternative tolabeling the antibody molecule, the presence of LAG-3 can be assayed ina sample by a competition immunoassay utilizing standards labeled with adetectable substance and an unlabeled antibody molecule. In this assay,the biological sample, the labeled standards and the antibody moleculeare combined and the amount of labeled standard bound to the unlabeledbinding molecule is determined. The amount of LAG-3 in the sample isinversely proportional to the amount of labeled standard bound to theantibody molecule.

Nucleic Acids

The invention also features nucleic acids comprising nucleotidesequences that encode heavy and light chain variable regions and CDRs ofthe anti-LAG-3 antibody molecules, as described herein. For example, theinvention features a first and second nucleic acid encoding heavy andlight chain variable regions, respectively, of an anti-LAG-3 antibodymolecule chosen from one or more of the antibody molecules disclosedherein. The nucleic acid can comprise a nucleotide sequence as set forthin the tables herein, or a sequence substantially identical thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, or which differs by no more than 3, 6, 15, 30, or 45nucleotides from the sequences shown in the tables herein.

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs from a heavy chainvariable region having an amino acid sequence as set forth in the tablesherein, or a sequence substantially homologous thereto (e.g., a sequenceat least about 85%, 90%, 95%, 99% or more identical thereto, and/orhaving one or more substitutions, e.g., conserved substitutions). Inother embodiments, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, or three CDRs from a light chain variableregion having an amino acid sequence as set forth in the tables herein,or a sequence substantially homologous thereto (e.g., a sequence atleast about 85%, 90%, 95%, 99% or more identical thereto, and/or havingone or more substitutions, e.g., conserved substitutions). In yetanother embodiment, the nucleic acid can comprise a nucleotide sequenceencoding at least one, two, three, four, five, or six CDRs from heavyand light chain variable regions having an amino acid sequence as setforth in the tables herein, or a sequence substantially homologousthereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or moreidentical thereto, and/or having one or more substitutions, e.g.,conserved substitutions).

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs from a heavy chainvariable region having the nucleotide sequence as set forth in thetables herein, a sequence substantially homologous thereto (e.g., asequence at least about 85%, 90%, 95%, 99% or more identical thereto,and/or capable of hybridizing under the stringency conditions describedherein). In another embodiment, the nucleic acid can comprise anucleotide sequence encoding at least one, two, or three CDRs from alight chain variable region having the nucleotide sequence as set forthin the tables herein, or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or capable of hybridizing under the stringency conditionsdescribed herein). In yet another embodiment, the nucleic acid cancomprise a nucleotide sequence encoding at least one, two, three, four,five, or six CDRs from heavy and light chain variable regions having thenucleotide sequence as set forth in the tables herein, or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or capable of hybridizingunder the stringency conditions described herein).

In another aspect, the application features host cells and vectorscontaining the nucleic acids described herein. The nucleic acids may bepresent in a single vector or separate vectors present in the same hostcell or separate host cell, as described in more detail hereinbelow.

Vectors

Further provided herein are vectors comprising nucleotide sequencesencoding an antibody molecule described herein. In one embodiment, thevectors comprise nucleotides encoding an antibody molecule describedherein. In one embodiment, the vectors comprise the nucleotide sequencesdescribed herein. The vectors include, but are not limited to, a virus,plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC).

Numerous vector systems can be employed. For example, one class ofvectors utilizes DNA elements which are derived from animal viruses suchas, for example, bovine papilloma virus, polyoma virus, adenovirus,vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV orMOMLV) or SV40 virus. Another class of vectors utilizes RNA elementsderived from RNA viruses such as Semliki Forest virus, Eastern EquineEncephalitis virus and Flaviviruses.

Additionally, cells which have stably integrated the DNA into theirchromosomes may be selected by introducing one or more markers whichallow for the selection of transfected host cells. The marker mayprovide, for example, prototropy to an auxotrophic host, biocideresistance, (e.g., antibiotics), or resistance to heavy metals such ascopper, or the like. The selectable marker gene can be either directlylinked to the DNA sequences to be expressed, or introduced into the samecell by cotransformation. Additional elements may also be needed foroptimal synthesis of mRNA. These elements may include splice signals, aswell as transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the constructs hasbeen prepared for expression, the expression vectors may be transfectedor introduced into an appropriate host cell. Various techniques may beemployed to achieve this, such as, for example, protoplast fusion,calcium phosphate precipitation, electroporation, retroviraltransduction, viral transfection, gene gun, lipid based transfection orother conventional techniques. In the case of protoplast fusion, thecells are grown in media and screened for the appropriate activity.

Methods and conditions for culturing the resulting transfected cells andfor recovering the antibody molecule produced are known to those skilledin the art, and may be varied or optimized depending upon the specificexpression vector and mammalian host cell employed, based upon thepresent description.

Cells

The invention also provides host cells comprising a nucleic acidencoding an antibody molecule as described herein.

In one embodiment, the host cells are genetically engineered to comprisenucleic acids encoding the antibody molecule.

In one embodiment, the host cells are genetically engineered by using anexpression cassette. The phrase “expression cassette,” refers tonucleotide sequences, which are capable of affecting expression of agene in hosts compatible with such sequences. Such cassettes may includea promoter, an open reading frame with or without introns, and atermination signal. Additional factors necessary or helpful in effectingexpression may also be used, such as, for example, an induciblepromoter.

The invention also provides host cells comprising the vectors describedherein.

The cell can be, but is not limited to, a eukaryotic cell, a bacterialcell, an insect cell, or a human cell. Suitable eukaryotic cellsinclude, but are not limited to, Vero cells, HeLa cells, COS cells, CHOcells, HEK293 cells, BHK cells, MDCKII cells and Per C6 cell line (e.g.,PER C6 cells from Crucell). Suitable insect cells include, but are notlimited to, Sf9 cells.

TABLE 1Amino acid and nucleotide sequences for murine, chimeric and humanized antibodymolecules. The antibody molecules include murine mAb BAP050, chimeric mAbs BAP050-chi,humanized mAbs BAP050-hum01 to BAP050-hum20, humanized mAbs BAP050-hum01-Ser toBAP050-hum15-Ser, BAP050-hum18-Ser to BAP050-hum20-Ser, and humanized mAbsBAP050-Clone-F to BAP050-Clone-J. The amino acid and nucleotide sequences of the heavyand light chain CDRs, the heavy and light chain variable regions, and the heave and lightchains are shown. BAP050 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 6 VH QIQLVQSGPELKKPGETVKISCKASGFTLTNYGMNWVRQTPGKGLKWMGWINTDTGEPTYADDFKGRFAF SLETSASTASLQINNLKNADTATYFCARNPPYYYGTNNAEAMDYWGQGTAVTVSS SEQ ID NO: 7 DNA VHCAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAA GAAGCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGAGGCAGACTCCAGGAAAGGGTTTAAAGTGGATGGGCTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGACGGTTTGCCTTCTCTTTGGAGACCTCTGCCAGCACTGCCTCTTTGCA GATCAACAACCTCAAAAATGCGGACACGGCTACATATTTCTGTGCAAGAAACCCCCCTTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGTCAAGGAACCGCAGTCACCGTCTCCTCA BAP050 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 16 VL DIQMTQTTSSLSASLGDRVTISCSSSQDISNYLNWYQQKPDGTVKVLIYYTSTLHLGVPSRFSGSGSGTD YSLTISNLELEDIATYYCQQYYNLPWTFGGGTKLEIK SEQ ID NO: 17 DNA VL GATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAAGTCCT GATCTATTACACATCAACCTTACACTTAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGAT TATTCTCTCACCATCAGCAACCTGGAACTCGAAGATATTGCCACATACTATTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGTGGAGGCACCAAGTTGGAAATCAAA BAP050-chi HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 20 VH QIQLVQSGPELKKPGETVKISCKASGFTLTNYGMNWVRQTPGKGLKWMGWINTDTGEPTYADDFKGRFAF SLETSASTASLQINNLKNADTATYFCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 21 DNA VHCAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAA GAAGCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGAGGCAGACTCCAGGAAAGGGTTTAAAGTGGATGGGCTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGACGGTTTGCCTTCTCTTTGGAGACCTCTGCCAGCACTGCCTCTTTGCA GATCAACAACCTCAAAAATGCGGACACGGCTACATATTTCTGTGCAAGAAACCCCCCTTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 22 HCQIQLVQSGPELKKPGETVKISCKASGFTLTNYGMN WVRQTPGKGLKWMGWINTDTGEPTYADDFKGRFAFSLETSASTASLQINNLKNADTATYFCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 23 DNA HCCAGATCCAGTTGGTGCAGTCTGGACCTGAGCTGAA GAAGCCTGGAGAGACAGTCAAGATCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGAGGCAGACTCCAGGAAAGGGTTTAAAGTGGATGGGCTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGACGGTTTGCCTTCTCTTTGGAGACCTCTGCCAGCACTGCCTCTTTGCA GATCAACAACCTCAAAAATGCGGACACGGCTACATATTTCTGTGCAAGAAACCCCCCTTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-chi LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 24 VL DIQMTQTTSSLSASLGDRVTISCSSSQDISNYLNWYQQKPDGTVKVLIYYTSTLHLGVPSRFSGSGSGTD YSLTISNLELEDIATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 25 DNA VL GATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAAGTCCT GATCTATTACACATCAACCTTACACTTAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGAT TATTCTCTCACCATCAGCAACCTGGAACTCGAAGATATTGCCACATACTATTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 26 LC DIQMTQTTSSLSASLGDRVTISCSSSQDISNYLNWYQQKPDGTVKVLIYYTSTLHLGVPSRFSGSGSGTD YSLTISNLELEDIATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 27 DNA LCGATATCCAGATGACACAGACTACATCCTCCCTGTC TGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGATGGAACTGTTAAAGTCCTGATCTATTACACATCAACCTTACACTTAGGAGTCC CATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGATTATTCTCTCACCATCAGCAACCTGGAACTCGAAGA TATTGCCACATACTATTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum01 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum01 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 33 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 35 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum02 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum02 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum03 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum03 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum04 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum04 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 44 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 45 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGAC TTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 46 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 47 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum05 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum05 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 48 VL EIVLTQSPATLSLSPGERATLSCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 49 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 50 LC EIVLTQSPATLSLSPGERATLSCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 51 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTC TTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum06 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum06 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 52 VL DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 53 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 54 LC DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 55 DNA LCGATATTGTGATGACCCAGACTCCACTCTCCCTGCC CGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum07 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum07 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 57 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACTATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 59 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACTATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum08 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum08 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum09 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 64 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 65 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 67 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum09 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum10 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 64 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 65 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 67 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum10 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum11 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 64 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 65 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 67 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum11 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 57 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACTATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 59 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACTATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum12 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 64 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 65 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 67 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum12 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum13 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 68 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 69 DNA VHCAGGTTCAGCTGGTGCAGTCCGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 70 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 71 DNA HCCAGGTTCAGCTGGTGCAGTCCGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum13 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum14 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 72 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 73 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 74 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 75 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum14 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum15 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 72 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 73 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 74 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 75 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum15 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum16 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 76 VH EVQLVQSGAEVKKPGESLRISCKGSGFTLTNYGMNWVRQATGQGLEWMGWINTDTGEPTYADDFKGRVTI SADKSISTAYLQWSSLKASDTAMYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 77 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAA AAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGAGTCACCATCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCA GTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 78 HCEVQLVQSGAEVKKPGESLRISCKGSGFTLTNYGMN WVRQATGQGLEWMGWINTDTGEPTYADDFKGRVTISADKSISTAYLQWSSLKASDTAMYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 79 DNA HCGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAA AAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGAGTCACCATCTCAGCCGACAAGTCCATCAGCACCGCCTACCTGCA GTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum16 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum17 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 80 VH QVQLVQSGSELKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISTLKAEDTATYFCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 81 DNA VHCAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAA GAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATTCACCCTGACTAACTATGGCATGAAT TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACACCGACACTGGGGAGCCAA CGTATGCCGATGACTTCAAGGGACGGTTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCACGCTAAAGGCTGAGGACACTGCTACATATTTCTGTGCAAGAAACCCCCCTTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 82 HCQVQLVQSGSELKKPGASVKVSCKASGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISTLKAEDTATYFCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 83 DNA HCCAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAA GAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATTCACCCTGACTAACTATGGCATGAAT TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACACCGACACTGGGGAGCCAA CGTATGCCGATGACTTCAAGGGACGGTTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCACGCTAAAGGCTGAGGACACTGCTACATATTTCTGTGCAAGAAACCCCCCTTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGACCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum17 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 84 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLQPEDIATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 85 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCT CCTCTAGTCAGGACATTAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCT GATCTACTATACATCCACTTTGCACCTGGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGAT TTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAACAGTATTATAATC TCCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 86 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLQPEDIATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 87 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCTCCTCTAGTCAGGACATTAGCAACTATTTAAATTGG TATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACTATACATCCACTTTGCACCTGGGGGTCC CATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGA TATTGCAACATATTACTGTCAACAGTATTATAATCTCCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum18 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum18 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 88 VL AIQLTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 89 DNA VL GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 90 LC AIQLTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 91 DNA LCGCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum19 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 28 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 29 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum19 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 92 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 94 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 95 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum20 HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 64 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 65 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 66 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQICSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 67 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCTGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum20 LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 96 VL DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 97 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGAC TTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 98 LC DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 99 DNA LCGATATTGTGATGACCCAGACTCCACTCTCCCTGCC CGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGATCC CAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum01-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum01-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 33 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 35 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum02-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum02-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 IQQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum03-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum03-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum04-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum04-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 44 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 45 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGAC TTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 46 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 47 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum05-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum05-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 48 VL EIVLTQSPATLSLSPGERATLSCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 49 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 50 LC EIVLTQSPATLSLSPGERATLSCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 51 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTC TTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum06-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum06-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 52 VL DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 53 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 54 LC DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 55 DNA LCGATATTGTGATGACCCAGACTCCACTCTCCCTGCC CGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum07-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum07-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 57 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACTATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 59 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACTATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum08-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum08-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum09-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 105 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 107 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum09-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum10-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 105 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 107 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum10-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum11-Ser HC SEQ ID NO: (Kabat) HCDR1 NYGMNSEQ ID NO: (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: (Chothia) HCDR1 GFTLTNY SEQ ID NO: (Chothia)HCDR2 NTDTGE SEQ ID NO: (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 104VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 105 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 107 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum11-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 57 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACTATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAA TTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 59 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACTATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum12-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 105 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 107 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum12-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum13-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 108 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 109 DNA VHCAGGTTCAGCTGGTGCAGTCCGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 110 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 111 DNA HCCAGGTTCAGCTGGTGCAGTCCGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum13-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 37 DNA VL GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT GATCTATTACACATCAACCTTACACTTAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGAT TTTACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 39 DNA LCGACATCCAGATGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTACACATCAACCTTACACTTAGGGATCC CACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGA TGCTGCATATTACTTCTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum14-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 8 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 9 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 18 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 19 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum14-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 40 VL EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 41 DNA VL GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 42 LC EIVLTQSPATLPVTLGQPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 43 DNA LCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum15-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 8 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 9 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 18 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WIRQSPSRGLEWLGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 19 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum15-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 60 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 61 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 62 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 63 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum18-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum18-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 88 VL AIQLTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 89 DNA VL GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAT TTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 90 LC AIQLTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 91 DNA LCGCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTC TGCATCTGTAGGAGACAGAGTCACCATCACTTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGA TTTTGCAACTTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum19-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 101 DNA VHGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 103 DNA HCGAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAA GAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGGTTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum19-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 92 VL EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGAT TTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 94 LC EIVLTQSPDFQSVTPKEKVTITCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 95 DNA LCGAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC TGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGGTCC CCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGA TGCTGCAACATATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-hum20-Ser HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 105 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 106 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 107 DNA HCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATTTACCCTCACAAACTATGGAATGAAC TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGTTGGATAAACACCGACACTGGAGAGCCAA CATATGCTGATGACTTCAAGGGAAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCACGGCATATCTGCA GATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGAAACCCTCCCTATTACTACGGT ACTAATAACGCGGAGGCTATGGACTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCCGCTTCCACCA AGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG CACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA GCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAG AGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTC TTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC CAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAGA AAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAG TGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCT TCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA BAP050-hum20-Ser LC SEQ ID NO: 10 (Kabat)LCDR1 SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHLSEQ ID NO: 12 (Kabat) LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1SQDISNY SEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3YYNLPW SEQ ID NO: 96 VL DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 97 DNA VL GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCA GTTCAAGTCAGGACATCAGCAATTATTTAAACTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT CATCTATTACACATCAACCTTACACTTAGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGAC TTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATTATAACC TTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 98 LC DIVMTQTPLSLPVTPGEPASISCSSSQDISNYLNWYQQKPGQAPRLLIYYTSTLHLGIPDRFSGSGSGTD FTLTISRLEPEDFAVYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 99 DNA LCGATATTGTGATGACCCAGACTCCACTCTCCCTGCC CGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGTTCAAGTCAGGACATCAGCAATTATTTAAACTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTACACATCAACCTTACACTTAGGGATCC CAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGA TTTTGCAGTGTATTACTGTCAGCAGTATTATAACCTTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA ATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAA CTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAA CGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATC AGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP050-Clone-F HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 112 DNA VHGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTCCGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 113 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 114 DNA HCGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTCCGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCA AGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCA GCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAG GGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGG TGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGC CAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCAC CAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGA GATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAG TGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCT TCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGT GATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone-F LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 32 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 115 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTT CCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCT GATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAC TTTACCTTCACCATCAGCTCCCTGGAAGCCGAGGACGCCGCCACCTACTACTGCCAGCAGTACTACAACC TGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 34 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGVPSRFSGSGSGTD FTFTISSLEAEDAATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 117 DNA LCGACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGG TATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCGTGC CCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGACTTTACCTTCACCATCAGCTCCCTGGAAGCCGAGGA CGCCGCCACCTACTACTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAA ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCA CCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTG AGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACC AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050-Clone-G HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 100 VH EVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 112 DNA VHGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTCCGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 113 HCEVQLVQSGAEVKKPGATVKISCKVSGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 114 DNA HCGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTCCGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCA AGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCA GCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAG GGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGG TGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGC CAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCAC CAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGA GATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAG TGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCT TCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGT GATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone-G LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 118 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTT CCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCT GATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGAC TTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGCAGTACTACAACC TGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 120 DNA LCGACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGG TATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCC CCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGA CGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAA ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCA CCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTG AGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACC AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCTGATGAATTC BAP050-Clone-H HC SEQ ID NO: 1 (Kabat) HCDR1NYGMN SEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat)HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 121 DNA VHCAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 122 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 123 DNA HCCAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCA AGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCA GCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAG GGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGG TGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGC CAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCAC CAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGA GATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAG TGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCT TCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGT GATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone-H LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 36 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 118 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTT CCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCT GATCTACTACACCTCCACCCTGCACCTGGGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGAC TTCACCCTGACCATCAACAACATCGAGTCCGAGGACGCCGCCTACTACTTCTGCCAGCAGTACTACAACC TGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 38 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTD FTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 120 DNA LCGACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGG TATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCC CCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGA CGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAA ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCA CCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTG AGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACC AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050-Clone-I HC SEQ ID NO: 1 (Kabat) HCDR1 NYGMNSEQ ID NO: 2 (Kabat) HCDR2 WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 4 (Chothia) HCDR1 GFTLTNYSEQ ID NO: 5 (Chothia) HCDR2 NTDTGE SEQ ID NO: 3 (Chothia) HCDR3NPPYYYGTNNAEAMDY SEQ ID NO: 104 VH QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSS SEQ ID NO: 124 DNA VHCAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAA GAAGCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCGGATTCACCCTCACCAATTACGGGATGAAC TGGGTCAGACAGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATTAACACCGACACCGGGGAGCCTA CCTACGCGGACGATTTCAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGTCCACCGCCTACCTCCA AATCTCCTCACTGAAAGCGGAGGACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTACTACTACGGA ACCAACAACGCCGAAGCCATGGACTACTGGGGCCAGGGCACCACTGTGACTGTGTCCAGC SEQ ID NO: 125 DNA VHCAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCT SEQ ID NO: 122 HCQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQARGQRLEWIGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 126 DNA HCCAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAA GAAGCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCCGGATTCACCCTCACCAATTACGGGATGAAC TGGGTCAGACAGGCCCGGGGTCAACGGCTGGAGTGGATCGGATGGATTAACACCGACACCGGGGAGCCTA CCTACGCGGACGATTTCAAGGGACGGTTCGTGTTCTCCCTCGACACCTCCGTGTCCACCGCCTACCTCCA AATCTCCTCACTGAAAGCGGAGGACACCGCCGTGTACTATTGCGCGAGGAACCCGCCCTACTACTACGGA ACCAACAACGCCGAAGCCATGGACTACTGGGGCCAGGGCACCACTGTGACTGTGTCCAGCGCGTCCACTA AGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGCCGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTG CCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTG CACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCAT CTAGCCTGGGTACCAAGACCTACACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCG CGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTC TTTCTGTTCCCACCGAAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCG TGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGC CAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCAT CAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAA AGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGA AATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATCGCCGTGGAA TGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGACTCAGACGGATCCT TCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGT GATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTCTCCCTGGGA SEQ ID NO: 127 DNA HCCAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA GAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGGCCTCTGGCTTCACCCTGACCAACTACGGCATGAAC TGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGCTGGATCAACACCGACACCGGCGAGCCTA CCTACGCCGACGACTTCAAGGGCAGATTCGTGTTCTCCCTGGACACCTCCGTGTCCACCGCCTACCTGCA GATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGGAACCCCCCTTACTACTACGGC ACCAACAACGCCGAGGCCATGGACTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCTGCTTCTACCA AGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTG CCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTG CACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCA GCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAG GGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTG TTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGG TGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGC CAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCAC CAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAA AGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGA GATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAG TGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCT TCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGT GATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP050-Clone-I LC SEQ ID NO: 10 (Kabat) LCDR1SSSQDISNYLN SEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat)LCDR3 QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNYSEQ ID NO: 14 (Chothia) LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPWSEQ ID NO: 56 VL DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 128 DNA VL GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTA GCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCTGCAGAAGCCCGGTCAATCACCTCAGCTGCT GATCTACTACACTAGCACCCTGCACCTGGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAG TTCACCCTGACTATCTCTAGCCTGCAGCCCGACGACTTCGCTACCTACTACTGTCAGCAGTACTATAACC TGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAG SEQ ID NO: 129 DNA VL GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTT CCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCT GATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAG TTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACC TGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAG SEQ ID NO: 58 LC DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTE FTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 130 DNA LCGATATTCAGATGACTCAGTCACCTAGTAGCCTGAG CGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGG TATCTGCAGAAGCCCGGTCAATCACCTCAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGCGTGC CCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGAGTTCACCCTGACTATCTCTAGCCTGCAGCCCGACGA CTTCGCTACCTACTACTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAG ATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCA CCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTG AGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACC AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC SEQ ID NO: 131 DNA LC GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTCTGCTTCCGTGGGCGACAGAGTGACCATCACCTGTT CCTCCAGCCAGGACATCTCCAACTACCTGAACTGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCT GATCTACTACACCTCCACCCTGCACCTGGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAG TTTACCCTGACCATCAGCTCCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGCAGTACTACAACC TGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCAT CTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTAC CCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCA CCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGA GAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC BAP050-Clone-J HCSEQ ID NO: 1 (Kabat) HCDR1 NYGMN SEQ ID NO: 2 (Kabat) HCDR2WINTDTGEPTYADDFKG SEQ ID NO: 3 (Kabat) HCDR3 NPPYYYGTNNAEAMDYSEQ ID NO: 4 (Chothia) HCDR1 GFTLTNY SEQ ID NO: 5 (Chothia) HCDR2 NTDTGESEQ ID NO: 3 (Chothia) HCDR3 NPPYYYGTNNAEAMDY SEQ ID NO: 108 VHQVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMN WVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYG TNNAEAMDYWGQGTTVTVSS SEQ ID NO: 132DNA VH CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAG CTAGTGGCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTG GATGGGCTGGATTAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTTAAGGGCAGATTCGTGTTT AGCCTGGACACTAGTGTGTCTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAGGACACCGCCGTCT ACTACTGCGCTAGAAACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTACTGGGGTCA AGGCACTACCGTGACCGTGTCTAGCSEQ ID NO: 133 DNA VH CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGG CCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATG GATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTC TCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGT ACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCA GGGCACCACCGTGACCGTGTCCTCTSEQ ID NO: 134 HC QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTYADDFKGRFVF SLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNV DHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQF NWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSEQ ID NO: 135 DNA HC CAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAACCCGGCGCTAGTGTGAAAGTCAGCTGTAAAG CTAGTGGCTTCACCCTGACTAACTACGGGATGAACTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTG GATGGGCTGGATTAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTTAAGGGCAGATTCGTGTTT AGCCTGGACACTAGTGTGTCTACCGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAGGACACCGCCGTCT ACTACTGCGCTAGAAACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTACTGGGGTCA AGGCACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGC CGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTGACCG TGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGCTCCGGGCT GTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTACACTTGCAACGTG GACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGCCCACCGTGCCCGCCTT GTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCGAAGCCCAAGGACACTTTGAT GATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCACAGGAAGATCCGGAGGTGCAGTTC AATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACCAAGCCGAGGGAGGAGCAGTTCAACTCCA CTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAGGACTGGCTGAACGGGAAGGAGTACAAGTGCAA AGTGTCCAACAAGGGACTTCCTAGCTCAATCGAAAAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAA CCCCAAGTGTATACCCTGCCACCGAGCCAGGAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTG TGAAGGGCTTCTACCCATCGGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAA GACCACCCCTCCGGTGCTGGACTCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGC AGATGGCAGGAGGGAAATGTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGA AGTCCCTGTCCCTCTCCCTGGGASEQ ID NO: 136 DNA HC CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGG CCTCTGGCTTCACCCTGACCAACTACGGCATGAACTGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATG GATGGGCTGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGCAGATTCGTGTTC TCCCTGGACACCTCCGTGTCCACCGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGT ACTACTGCGCCCGGAACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTATTGGGGCCA GGGCACCACCGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCC AGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCG TGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCT GTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTG GACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCT GCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGAT GATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCA CCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAA GGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAG CCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGG TGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAA GACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCC AGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGA AGAGCCTGAGCCTGTCCCTGGGCBAP050-Clone-J LC SEQ ID NO: 10 (Kabat) LCDR1 SSSQDISNYLNSEQ ID NO: 11 (Kabat) LCDR2 YTSTLHL SEQ ID NO: 12 (Kabat) LCDR3QQYYNLPWT SEQ ID NO: 13 (Chothia) LCDR1 SQDISNY SEQ ID NO: 14 (Chothia)LCDR2 YTS SEQ ID NO: 15 (Chothia) LCDR3 YYNLPW SEQ ID NO: 36 VLDIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNW YQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVE IK SEQ ID NO: 137 DNA VLGATATTCAGATGACTCAGTCACCTAGTAGCCTGAG CGCTAGTGTGGGCGATAGAGTGACTATCACCTGTAGCTCTAGTCAGGATATCTCTAACTACCTGAACTGG TATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTACACTAGCACCCTGCACCTGGGAATCC CCCCTAGGTTTAGCGGTAGCGGCTACGGCACCGACTTCACCCTGACTATTAACAATATCGAGTCAGAGGA CGCCGCCTACTACTTCTGTCAGCAGTACTATAACCTGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAG ATTAAG SEQ ID NO: 118 DNA VLGACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGG TATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCC CCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGA CGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAA ATCAAG SEQ ID NO: 38 LCDIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNW YQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 138 DNA LC GATATTCAGATGACTCAGTCACCTAGTAGCCTGAGCGCTAGTGTGGGCGATAGAGTGACTATCACCTGTA GCTCTAGTCAGGATATCTCTAACTACCTGAACTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCT GATCTACTACACTAGCACCCTGCACCTGGGAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGGCACCGAC TTCACCCTGACTATTAACAATATCGAGTCAGAGGACGCCGCCTACTACTTCTGTCAGCAGTACTATAACC TGCCCTGGACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTGTTCAT CTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTAC CCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCA CCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGA GAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC SEQ ID NO: 139 DNA LCGACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGTTCCTCCAGCCAGGACATCTCCAACTACCTGAACTGG TATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTACTACACCTCCACCCTGCACCTGGGCATCC CCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGTCCGAGGA CGCCGCCTACTACTTCTGCCAGCAGTACTACAACCTGCCCTGGACCTTCGGCCAGGGCACCAAGGTGGAA ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCA CCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAA CGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTG AGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACC AGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACAGGGGCGAGTGC BAP050 HC SEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAACSEQ ID NO: 141 (Kabat) HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGCTGATGACTTCAAGGGA SEQ ID NO: 142 (Kabat) HCDR3AACCCCCCTTATTACTACGGTACTAATAACGCGGA GGCTATGGACTACSEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 142 (Chothia) HCDR3 AACCCCCCTTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-chi HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 142 (Kabat) HCDR3 AACCCCCCTTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 142 (Chothia) HCDR3 AACCCCCCTTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-chi LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum01 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum01 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum02 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum02 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum03 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum03 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum04 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum04 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum05 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum05 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum06 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum06 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum07 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum07 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum08 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum08 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum09 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum09 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum10 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum10 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum11 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum11 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum12 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum12 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum13 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum13 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum14 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum14 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum15 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum15 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum16 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum16 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum17 HCSEQ ID NO: 152 (Kabat) HCDR1 AACTATGGCATGAAT SEQ ID NO: 153 (Kabat)HCDR2 TGGATCAACACCGACACTGGGGAGCCAACGTATGC CGATGACTTCAAGGGASEQ ID NO: 142 (Kabat) HCDR3 AACCCCCCTTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 154 (Chothia) HCDR1 GGATTCACCCTGACTAACTATSEQ ID NO: 155 (Chothia) HCDR2 AACACCGACACTGGGGAGSEQ ID NO: 142 (Chothia) HCDR3 AACCCCCCTTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum17 LC SEQ ID NO: 156 (Kabat) LCDR1TCCTCTAGTCAGGACATTAGCAACTATTTAAAT SEQ ID NO: 157 (Kabat) LCDR2TATACATCCACTTTGCACCTG SEQ ID NO: 158 (Kabat) LCDR3CAACAGTATTATAATCTCCCTTGGACG SEQ ID NO: 159 (Chothia) LCDR1AGTCAGGACATTAGCAACTAT SEQ ID NO: 160 (Chothia) LCDR2 TATACATCCSEQ ID NO: 161 (Chothia) LCDR3 TATTATAATCTCCCTTGG BAP050-hum18 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum18 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum19 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum19 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum20 HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum20 LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum01-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum01-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum02-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum02-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum03-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum03-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum04-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum04-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum05-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum05-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum06-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum06-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum07-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum07-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum08-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum08-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum09-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum09-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum10-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum10-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum11-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum11-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum12-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum12-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum13-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum13-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum14-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum14-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum15-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum15-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum18-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum18-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum19-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum19-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-hum20-Ser HCSEQ ID NO: 140 (Kabat) HCDR1 AACTATGGAATGAAC SEQ ID NO: 141 (Kabat)HCDR2 TGGATAAACACCGACACTGGAGAGCCAACATATGC TGATGACTTCAAGGGASEQ ID NO: 151 (Kabat) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC SEQ ID NO: 143 (Chothia) HCDR1 GGATTTACCCTCACAAACTATSEQ ID NO: 144 (Chothia) HCDR2 AACACCGACACTGGAGAGSEQ ID NO: 151 (Chothia) HCDR3 AACCCTCCCTATTACTACGGTACTAATAACGCGGAGGCTATGGACTAC BAP050-hum20-Ser LC SEQ ID NO: 145 (Kabat) LCDR1AGTTCAAGTCAGGACATCAGCAATTATTTAAAC SEQ ID NO: 146 (Kabat) LCDR2TACACATCAACCTTACACTTA SEQ ID NO: 147 (Kabat) LCDR3CAGCAGTATTATAACCTTCCGTGGACG SEQ ID NO: 148 (Chothia) LCDR1AGTCAGGACATCAGCAATTAT SEQ ID NO: 149 (Chothia) LCDR2 TACACATCASEQ ID NO: 150 (Chothia) LCDR3 TATTATAACCTTCCGTGG BAP050-Clone-F HCSEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Kabat)HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGC CGACGACTTCAAGGGCSEQ ID NO: 164 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTACSEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAGSEQ ID NO: 164 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050-Clone-F LC SEQ ID NO: 167 (Kabat) LCDR1TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 168 (Kabat) LCDR2TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Kabat) LCDR3CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1AGCCAGGACATCTCCAACTAC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCCSEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG BAP050-Clone-G HCSEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Kabat)HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGC CGACGACTTCAAGGGCSEQ ID NO: 164 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTACSEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAGSEQ ID NO: 164 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050-Clone-G LC SEQ ID NO: 167 (Kabat) LCDR1TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 168 (Kabat) LCDR2TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Kabat) LCDR3CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1AGCCAGGACATCTCCAACTAC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCCSEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG BAP050-Clone-H HCSEQ ID NO: 162 (Kabat) HCDR1 AACTACGGCATGAAC SEQ ID NO: 163 (Kabat)HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGC CGACGACTTCAAGGGCSEQ ID NO: 164 (Kabat) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT SEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTACSEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAGSEQ ID NO: 164 (Chothia) HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGAGGCCATGGACTAT BAP050-Clone-H LC SEQ ID NO: 167 (Kabat) LCDR1TCCTCCAGCCAGGACATCTCCAACTACCTGAAC SEQ ID NO: 168 (Kabat) LCDR2TACACCTCCACCCTGCACCTG SEQ ID NO: 169 (Kabat) LCDR3CAGCAGTACTACAACCTGCCCTGGACC SEQ ID NO: 170 (Chothia) LCDR1AGCCAGGACATCTCCAACTAC SEQ ID NO: 171 (Chothia) LCDR2 TACACCTCCSEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG BAP050-Clone-I HCSEQ ID NO: 173 (Kabat) HCDR1 AATTACGGGATGAAC SEQ ID NO: 162 (Kabat)HCDR1 AACTACGGCATGAAC SEQ ID NO: 174 (Kabat) HCDR2TGGATTAACACCGACACCGGGGAGCCTACCTACGC GGACGATTTCAAGGGASEQ ID NO: 163 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 175 (Kabat) HCDR3AACCCGCCCTACTACTACGGAACCAACAACGCCGA AGCCATGGACTAC SEQ ID NO: 164 (Kabat)HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGA GGCCATGGACTATSEQ ID NO: 176 (Chothia) HCDR1 GGATTCACCCTCACCAATTACSEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTACSEQ ID NO: 177 (Chothia) HCDR2 AACACCGACACCGGGGAGSEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAGSEQ ID NO: 175 (Chothia) HCDR3 AACCCGCCCTACTACTACGGAACCAACAACGCCGAAGCCATGGACTAC SEQ ID NO: 164 (Chothia) HCDR3AACCCCCCTTACTACTACGGCACCAACAACGCCGA GGCCATGGACTAT BAP050-Clone-I LCSEQ ID NO: 178 (Kabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAACSEQ ID NO: 167 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAACSEQ ID NO: 179 (Kabat) LCDR2 TACACTAGCACCCTGCACCTGSEQ ID NO: 168 (Kabat) LCDR2 TACACCTCCACCCTGCACCTGSEQ ID NO: 180 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACCSEQ ID NO: 169 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACCSEQ ID NO: 181 (Chothia) LCDR1 AGTCAGGATATCTCTAACTACSEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTACSEQ ID NO: 182 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 171 (Chothia) LCDR2TACACCTCC SEQ ID NO: 183 (Chothia) LCDR3 TACTATAACCTGCCCTGGSEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG BAP050-Clone-J HCSEQ ID NO: 184 (Kabat) HCDR1 AACTACGGGATGAAC SEQ ID NO: 162 (Kabat)HCDR1 AACTACGGCATGAAC SEQ ID NO: 185 (Kabat) HCDR2TGGATTAACACCGACACCGGCGAGCCTACCTACGC CGACGACTTTAAGGGCSEQ ID NO: 163 (Kabat) HCDR2 TGGATCAACACCGACACCGGCGAGCCTACCTACGCCGACGACTTCAAGGGC SEQ ID NO: 186 (Kabat) HCDR3AACCCCCCCTACTACTACGGCACTAACAACGCCGA GGCTATGGACTAC SEQ ID NO: 164 (Kabat)HCDR3 AACCCCCCTTACTACTACGGCACCAACAACGCCGA GGCCATGGACTATSEQ ID NO: 287 (Chothia) HCDR1 GGCTTCACCCTGACTAACTACSEQ ID NO: 165 (Chothia) HCDR1 GGCTTCACCCTGACCAACTACSEQ ID NO: 177 (Chothia) HCDR2 AACACCGACACCGGGGAGSEQ ID NO: 166 (Chothia) HCDR2 AACACCGACACCGGCGAGSEQ ID NO: 186 (Chothia) HCDR3 AACCCCCCCTACTACTACGGCACTAACAACGCCGAGGCTATGGACTAC SEQ ID NO: 164 (Chothia) HCDR3AACCCCCCTTACTACTACGGCACCAACAACGCCGA GGCCATGGACTAT BAP050-Clone-J LCSEQ ID NO: 178 (Kabat) LCDR1 AGCTCTAGTCAGGATATCTCTAACTACCTGAACSEQ ID NO: 167 (Kabat) LCDR1 TCCTCCAGCCAGGACATCTCCAACTACCTGAACSEQ ID NO: 179 (Kabat) LCDR2 TACACTAGCACCCTGCACCTGSEQ ID NO: 168 (Kabat) LCDR2 TACACCTCCACCCTGCACCTGSEQ ID NO: 180 (Kabat) LCDR3 CAGCAGTACTATAACCTGCCCTGGACCSEQ ID NO: 169 (Kabat) LCDR3 CAGCAGTACTACAACCTGCCCTGGACCSEQ ID NO: 181 (Chothia) LCDR1 AGTCAGGATATCTCTAACTACSEQ ID NO: 170 (Chothia) LCDR1 AGCCAGGACATCTCCAACTACSEQ ID NO: 182 (Chothia) LCDR2 TACACTAGC SEQ ID NO: 171 (Chothia) LCDR2TACACCTCC SEQ ID NO: 183 (Chothia) LCDR3 TACTATAACCTGCCCTGGSEQ ID NO: 172 (Chothia) LCDR3 TACTACAACCTGCCCTGG

TABLE 2Amino acid and nucleotide sequences of the heavy and light chain framework regionsfor humanized mAbs BAP050-hum01 to BAP050-hum20, BAP050-hum01-Ser to BAP050-hum15-Ser, BAP050-hum18-Ser to BAP050-hum20-Ser, and BAP050-Clone-F to BAP050-Clone-J Amino Acid Sequence Nucleotide Sequence VHFW1EVQLVQSGAEVKKPGATVKISCKVS GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAA (type a)(SEQ ID NO: 187) GAAACCCGGCGCTACCGTGAAGATCTCCTGCAAGGTGTCC (SEQ ID NO: 188) GAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCTACAGTGAAAATCTCCTGCAAGG TTTCT (SEQ ID NO: 189) VHFW1QVQLVQSGAEVKKPGASVKVSCKAS CAAGTGCAGCTGGTGCAGTCGGGAGCCGAAGTGAA (type b)(SEQ ID NO: 190) GAAGCCTGGAGCCTCGGTGAAGGTGTCGTGCAAGGCATCC (SEQ ID NO: 191) CAGGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAACCTGGCGCCTCCGTGAAGGTGTCCTGCAAGG CCTCT (SEQ ID NO: 192)CAGGTTCAGCTGGTGCAGTCCGGAGCTGAGGTGAA GAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT (SEQ ID NO: 193) VHFW1 EVQLVQSGAEVKKPGESLRISCKGSGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAA (type c) (SEQ ID NO: 194)AAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGG GTTCT (SEQ ID NO: 195) VHFW1QVQLVQSGSELKKPGASVKVSCKAS CAGGTGCAGCTGGTGCAATCTGGGTCTGAGTTGAA (type d)(SEQ ID NO: 196) GAAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCTTCT (SEQ ID NO: 197) VHFW2 WVRQAPGQGLEWMGTGGGTCCGCCAGGCCCCAGGTCAAGGCCTCGAGTG (type a) (SEQ ID NO: 198)GATGGGC (SEQ ID NO: 199) TGGGTGCGACAGGCCCCTGGACAGGGCCTGGAATGGATGGGC (SEQ ID NO: 200) TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGT (SEQ ID NO: 201) VHFW2 WVRQARGQRLEWIGTGGGTCAGACAGGCCCGGGGTCAACGGCTGGAGTG (type b) (SEQ ID NO: 202)GATCGGA (SEQ ID NO: 203) TGGGTGCGACAGGCCAGGGGCCAGCGGCTGGAATGGATCGGC (SEQ ID NO: 204) TGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGT (SEQ ID NO: 205) VHFW2 WIRQSPSRGLEWLGTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTG (type c) (SEQ ID NO: 206)GCTGGGT (SEQ ID NO: 207) VHFW2 WVRQATGQGLEWMGTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTG (type d) (SEQ ID NO: 208)GATGGGT (SEQ ID NO: 209) VHFW3 RFVFSLDTSVSTAYLQICSLKAEDTAGATTTGTCTTCTCCTTGGACACCTCTGTCAGCAC (type a) AVYYCAR (SEQ ID NO: 210)GGCATATCTGCAGATCTGCAGCCTAAAGGCTGAGG ACACTGCCGTGTATTACTGTGCAAGA(SEQ ID NO: 211) VHFW3 RFVFSLDTSVSTAYLQISSLKAEDTCGGTTCGTGTTCTCCCTCGACACCTCCGTGTCCAC (type a- AVYYCAR (SEQ ID NO: 212)CGCCTACCTCCAAATCTCCTCACTGAAAGCGGAGG Ser)ACACCGCCGTGTACTATTGCGCGAGG SEQ ID NO: 213)AGATTCGTGTTTAGCCTGGACACTAGTGTGTCTAC CGCCTACCTGCAGATCTCTAGCCTGAAGGCCGAGGACACCGCCGTCTACTACTGCGCTAGA SEQ ID NO: 214)AGATTCGTGTTCTCCCTGGACACCTCCGTGTCCAC CGCCTACCTGCAGATCTCCAGCCTGAAGGCCGAGGATACCGCCGTGTACTACTGCGCCCGG (SEQ ID NO: 215)AGATTTGTCTTCTCCTTGGACACCTCTGTCAGCAC GGCATATCTGCAGATCAGCAGCCTAAAGGCTGAGGACACTGCCGTGTATTACTGTGCAAGA (SEQ ID NO: 216) VHFW3RVTISADKSISTAYLQWSSLKASDT AGAGTCACCATCTCAGCCGACAAGTCCATCAGCAC (type b)AMYYCAR (SEQ ID NO: 217) CGCCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTACTGTGCAAGA (SEQ ID NO: 218) VHFW3RFVFSLDTSVSTAYLQISTLKAEDT CGGTTTGTCTTCTCCTTGGACACCTCTGTCAGCAC (type c)ATYFCAR (SEQ ID NO: 219) GGCATATCTGCAGATCAGCACGCTAAAGGCTGAGGACACTGCTACATATTTCTGTGCAAGA (SEQ ID NO: 220) VHFW4 WGQGTTVTVSSTGGGGCCAGGGCACCACTGTGACTGTGTCCAGC (SEQ ID NO: 221) (SEQ ID NO: 222)TGGGGTCAAGGCACTACCGTGACCGTGTCTAGC (SEQ ID NO: 223)TGGGGCCAGGGCACCACCGTGACCGTGTCCTCT (SEQ ID NO: 224)TGGGGCCAGGGCACCACCGTGACCGTGTCCTCC (SEQ ID NO: 225) VLFW1DIQMTQSPSSLSASVGDRVTITC GATATTCAGATGACTCAGTCACCTAGTAGCCTGAG (type a)(SEQ ID NO: 226) CGCTAGTGTGGGCGATAGAGTGACTATCACCTGT (SEQ ID NO: 227)GACATCCAGATGACCCAGTCCCCCTCCAGCCTGTC TGCTTCCGTGGGCGACAGAGTGACCATCACCTGT(SEQ ID NO: 228) GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGC (SEQ ID NO: 229) VLFW1EIVLTQSPATLPVTLGQPASISC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGCC (type b)(SEQ ID NO: 230) CGTCACCCTTGGACAGCCGGCCTCCATCTCCTGC (SEQ ID NO: 231)VLFW1 EIVLTQSPATLSLSPGERATLSC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTC(type c) (SEQ ID NO: 232) TTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGC(SEQ ID NO: 233) VLFW1 DIVMTQTPLSLPVTPGEPASISCGATATTGTGATGACCCAGACTCCACTCTCCCTGCC (type d) (SEQ ID NO: 234)CGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGC (SEQ ID NO: 235) VLFW1EIVLTQSPDFQSVTPKEKVTITC GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTC (type e)(SEQ ID NO: 236) TGTGACTCCAAAGGAGAAAGTCACCATCACCTGC (SEQ ID NO: 237)VLFW1 AIQLTQSPSSLSASVGDRVTITC GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTC(type f) (SEQ ID NO: 238) TGCATCTGTAGGAGACAGAGTCACCATCACTTGC(SEQ ID NO: 239) VLFW2 WYQQKPGKAPKLLIYTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCT (type a) (SEQ ID NO: 240)GCTGATCTAC (SEQ ID NO: 241) TGGTATCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTAC (SEQ ID NO: 242) TGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTAT (SEQ ID NO: 243) VLFW2 WYQQKPGQAPRLLIY (SEQ IDTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCT (type b) NO: 244)CCTCATCTAT (SEQ ID NO: 245) VLFW2 WYLQKPGQSPQLLIY (SEQ IDTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCT (type c) NO: 246)CCTGATCTAT (SEQ ID NO: 247) VLFW2 WYLQKPGQSPQLLIYTGGTATCTGCAGAAGCCCGGTCAATCACCTCAGCT (type d) (SEQ ID NO: 248)GCTGATCTAC (SEQ ID NO: 249) TGGTATCTGCAGAAGCCCGGCCAGTCCCCTCAGCTGCTGATCTAC (SEQ ID NO: 250) TGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTAT (SEQ ID NO: 251) VLFW3 GVPSRFSGSGSGTDFTFTISSLEAEGGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGG (type a) DAATYYC (SEQ ID NO: 252)CACCGACTTTACCTTCACCATCAGCTCCCTGGAAG CCGAGGACGCCGCCACCTACTACTGC (SEQ IDNO: 253) GGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAG CTGAAGATGCTGCAACATATTACTGT (SEQ IDNO: 254) VLFW3 GIPPRFSGSGYGTDFTLTINNIESEGGAATCCCCCCTAGGTTTAGCGGTAGCGGCTACGG (type b) DAAYYFC (SEQ ID NO: 255)CACCGACTTCACCCTGACTATTAACAATATCGAGT CAGAGGACGCCGCCTACTACTTCTGT (SEQ IDNO: 256) GGCATCCCCCCTAGATTCTCCGGCTCTGGCTACGGCACCGACTTCACCCTGACCATCAACAACATCGAGT CCGAGGACGCCGCCTACTACTTCTGC (SEQ IDNO: 257) GGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAAT CTGAGGATGCTGCATATTACTTCTGT (SEQ IDNO: 258) VLFW3 GIPDRFSGSGSGTDFTLTISRLEPEGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGG (type c) DFAVYYC (SEQ ID NO: 259)GACAGACTTCACTCTCACCATCAGCAGACTGGAGC CTGAAGATTTTGCAGTGTATTACTGT (SEQ IDNO: 260) VLFW3 GVPSRFSGSGSGTEFTLTISSLQPDGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGG (type d) DFATYYC (SEQ ID NO: 261)CACCGAGTTCACCCTGACTATCTCTAGCCTGCAGC CCGACGACTTCGCTACCTACTACTGT (SEQ IDNO: 262) GGCGTGCCCTCCAGATTTTCCGGCTCTGGCTCTGGCACCGAGTTTACCCTGACCATCAGCTCCCTGCAGC CCGACGACTTCGCCACCTACTACTGC (SEQ IDNO: 263) GGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGC CTGATGATTTTGCAACTTATTACTGT (SEQ IDNO: 264) VLFW3 GVPSRFSGSGSGTDFTLTISSLQPEGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGG (type e) DFATYYC (SEQ ID NO: 265)GACAGATTTCACTCTCACCATCAGCAGCCTGCAGC CTGAAGATTTTGCAACTTATTACTGT (SEQ IDNO: 266) VLFW3 GVPSRFSGSGSGTDFTFTISSLQPEGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGG (type f) DIATYYC (SEQ ID NO: 267)GACAGATTTTACTTTCACCATCAGCAGCCTGCAGC CTGAAGATATTGCAACATATTACTGT (SEQ IDNO: 268) VLFW3 GIPDRFSGSGSGTDFTLTISRLEPEGGGATCCCAGACAGGTTCAGTGGCAGTGGGTCTGG (type g) DFAVYYC (SEQ ID NO: 269)GACAGACTTCACTCTCACCATCAGCAGACTGGAGC CTGAAGATTTTGCAGTGTATTACTGT (SEQ IDNO: 270) VLFW4 FGQGTKVEIK (SEQ ID NO:TTCGGTCAAGGCACTAAGGTCGAGATTAAG (SEQ 271) ID NO: 272)TTCGGCCAGGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 273)TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 274)

TABLE 3Constant region amino acid sequences of human IgG heavy chains and human kappalight chain HCIgG4 (S228P) mutant constant region amino acid sequence (EU Numbering)ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSVFLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTYRVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEGNVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID NO: 275) LCHuman kappa constant region amino acid sequenceRTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQDSKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO: 276) HCIgG4 (S228P) mutant constant region amino acid sequence lacking theC-terminal Lysine (K) (EU Numbering)ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCP APEFLGGPSVFLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTK PREEQFNSTYRVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYT LPPSQEEMTKNQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEGNVFSCSVMHE ALHNHYTQKS LSLSLG (SEQ ID NO: 277) HC IgG1 wild type ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGGPSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYNSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRWQQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 278) HCIgG1 (N297A) mutant constant region amino acid sequence (EU Numbering)ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGGPSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYASTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRWQQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 279) HCIgG1 (D265A, P329A) mutant constant region amino acid sequence (EU Numbering)ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGGPSVFLFPPKP KDTLMISRTP EVTCVVVAVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYNSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LAAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRWQQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 280) HCIgG1 (L234A, L235A) mutant constant region amino acid sequence (EU Numbering)ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGGPSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYNSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRWQQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 281)

TABLE 4 Amino acid sequences of the heavy and light chainleader sequences for humanized mAbs BAP050- Clone-F to BAP050-Clone-JBAP050-Clone-F HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-F LCMSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-G HCMEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-G LCMSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-H HCMEWSWVFLFFLSVTTGVHS (SEQ ID NO: 282) BAP050-Clone-H LCMSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-I HCMAWVWTLPFLMAAAQSVQA (SEQ ID NO: 284) MEWSWVFLFFLSVTTGVHS(SEQ ID NO: 282) BAP050-Clone-I LC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 285)MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283) BAP050-Clone-J HCMAWVWTLPFLMAAAQSVQA (SEQ ID NO: 284) MEWSWVFLFFLSVTTGVHS(SEQ ID NO: 282) BAP050-Clone-J LC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 285)MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 283)

Table 5. See Examples.

Table 6. See Examples.

TABLE 7 Selected therapeutic agents that can be administered incombination with the anti- LAG-3 antibody molecules, e.g., as a singleagent or in combination with other immunomodulators described herein.Each publication listed in this Table is herein incorporated byreference in its entirety, including all structural formulae therein.Com- Generic Patents/Patent pound Name Application No. TradenameCompound Structure Publications A1 Sotrastaurin

EP 1682103 US 2007/142401 WO 2005/039549 A2 Nilotinib HCl monohydrateTASIGNA ®

WO 2004/005281 US 7,169,791 HCl • H₂O A3

WO 2010/060937 WO 2004/072051 EP 1611112 US 8,450,310 A4 Dactolisib

WO 2006/122806 A5

US 8,552,002 A6 Buparlisib

WO 2007/084786 A7

WO 2009/141386 US 2010/0105667 A8

WO 2010/029082 A9 CYP17 inhibitor WO 2010/149755 US 8,263,635 B2 EP2445903 B1 A10

WO 2011/076786 A11 Deferasirox EXJADE ®

WO 1997/049395 A12 Letrozole FEMARA ®

US 4,978,672 A13

WO 2013/124826 US 2013/0225574 A14

WO 2013/111105 A15

WO 2005/073224 A16 Imatinib mesylate GLEEVEC ®

WO 1999/003854 Mesylate A17

EP 2099447 US 7,767,675 US 8,420,645 Dihydrochloric salt A18 RuxolitinibPhosphate JAKAFI ®

WO 2007/070514 EP 2474545 US 7,598,257 WO 2014/018632 H₃PO₄ A19Panobinostat

WO 2014/072493 WO 2002/022577 EP 1870399 A20 Osilodrostat

WO 2007/024945 A21

WO 2008/016893 EP 2051990 US 8,546,336 A22 Sonidegib phosphate

WO 2007/131201 EP 2021328 US 8,178,563 A23 ceritinib ZYKADIA ™

WO 2008/073687 US 8,039,479 A24

US 8,415,355 US 8,685,980 A25

WO 2010/007120 A26 Human monoclonal antibody to PRLR US 7,867,493 A27

WO 2010/026124 EP 2344474 US 2010/0056576 WO 2008/106692 A28

WO 2010/101849 A29 Encorafenib

WO 2011/025927 A30

WO 2011/101409 A31 Human monoclonal antibody to HER3 WO 2012/022814 EP2606070 US 8,735,551 A32 Antibody Drug Conjugate (ADC) WO 2014/160160Ab: 12425 (see Table 1, paragraph [00191]) Linker: SMCC (see paragraph[00117] Payload: DM1 (see paragraph [00111] See also Claim 29 A33Monoclonal antibody or Fab to M-CSF WO 2004/045532 A34 Binimetinib

WO 2003/077914 A35 Midostaurin

WO 2003/037347 EP 1441737 US 2012/252785 A36 Everolimus AFINITOR ®

WO 2014/085318 A37

WO 2007/030377 US 7,482,367 A38 Pasireotide diaspartate SIGNIFOR ®

WO 2002/010192 US 7,473,761 A39 Dovitinib

WO 2009/115562 US 8,563,556 A40

WO 2013/184757 A41

WO 2006/122806 A42

WO 2008/073687 US 8,372,858 A43

WO 2010/002655 US 8,519,129 A44

WO 2010/002655 US 8,519,129 A45

WO 2010/002655 A46 Valspodar AMDRAY ™

EP 296122 A47 Vatalanib succinate

WO 98/35958 succinate A48 IDH inhibitor WO 2014/141104 A49 BCR-ABLinhibitor WO 2013/171639 WO 2013/171640 WO 2013/171641 WO 2013/171642A50 cRAF inhibitor WO 2014/151616 A51 ERK 1/2 ATP competitive inhibitorPCT/US 2014/062913

EXAMPLES

The Examples below are set forth to aid in the understanding of theinventions but are not intended to, and should not be construed to,limit its scope in any way.

Example 1: Humanization of Anti-LAG-3 Antibody, BAP050

A murine anti-LAG-3 monoclonal antibody, BAP050, was humanized. Thesequences and test samples of twenty humanized BAP050 clones with uniquevariable region sequences were obtained. These clones were furtheranalyzed for their biological functions (e.g., antigen binding andligand blocking), structural features, and transient expression in CHOcells.

Example 1.1: Humanization Technology and Process

Humanization of BAP050 was performed using a combinatorial library ofhuman germ line variable region frameworks (FWs). The technology entailstransferring the murine CDRs in frame to a library of human variableregions (VRs) that had been constructed by randomly combining human germline FW1, FW2 and FW3 sequences. Only one FW4 sequence is used, which isWGQGTTVTVSS (SEQ ID NO: 221) for the heavy chain (HC) (Kabat human HCsubgroup I, No. 21) and FGQGTKVEIK (SEQ ID NO: 271) for the light chain(LC) (Kabat human κ subgroup I, No. 5). The library of VR sequences isfused to human constant region (CR) sequences, human IgG4(S228P) of HCand human κ CR of LC, and the resulting library of whole IgG isexpressed in CHO cells for screening. Screening was performed withtissue culture supernatants measuring binding avidity onantigen-expressing cells in a whole cell ELISA format or on FACS.

The humanization process was performed in a stepwise manner startingwith the construction and expression of the appropriate chimeric mAb(murine VR, IgG4(S228P), human κ), which can serve as a comparator forthe screening of the humanized clones. The constant region amino acidsequences for human IgG4(S228P) heavy chain and human kappa light chainare shown in Table 6.

Humanization of the VR of LC and HC were performed in two independentsteps. The library of humanized LC (huLC) was paired with the chimericHC (murine VR, IgG4(S228P)) and the resulting “half-humanized” mAbs werescreened for binding activity by ELISA. The huLC of clones with adequatebinding activity (≧binding of chimeric mAb) were selected. Analogously,the library of humanized HC (huHC) was paired with the chimeric LC(murine VR, human κ) and screened for binding activity by ELISA. ThehuHC of clones with appropriate binding activity (≧binding of chimericmAb) were selected.

The variable regions of the selected huLC and huHC were then sequencedto identify the huLC and huHC with unique sequences (some clones fromthe initial selection process may share the same LC or HC). The uniquehuLC and huHC were then randomly combined to form a small library ofhumAbs, which was expressed in CHO cells and screened onantigen-expressing cells in an ELISA and FACS format. Clones withbinding activities that were equal or better than the binding of thechimeric comparator mAb are the final product of the humanizationprocess.

Example 1.2: Sequence of Murine mAb BAP050

The LC and HC variable region sequences of the murine anti-LAG-3 mAbwere determined. The sequences obtained from two independent analyseswere identical and are shown in FIG. 1.

Germline analysis was performed and part of the result is shown in FIG.2 as an amino acid sequence alignment. For the light chain, the V-geneis 96.88% identical to mIGkV10-94*01F (279/288 nts) and the J-gene is97.30% identical to mIGkJ1*01F (36/37 nts). For the heavy chain, theV-gene is 96.88% identical to mIGHV9-3-1*01F (279/288 nts), the J-geneis 86.79% identical to mIGHJ4*01F, and the D-gene is mIGHD1-1*01F.

Example 1.3: Humanized Antibody Clones

As shown in FIG. 3, the process of humanization yielded twenty humanizedclones with binding affinities comparable to that of the chimericantibody. In addition to binding data, for each clone, the VR sequenceswere provided along with a sample of the mAb. The samples had beenprepared by transient transfections of CHO cells and were concentratedtissue culture supernatants. The mAb concentrations in the solutions hadbeen determined by an IgG4-specific ELISA.

As shown in FIG. 4, the twenty unique clones are combinations of sixunique HC and twelve unique LC. The amino acid and nucleotide sequencesof the heavy and light chain variable domains for the humanized BAP050clones are shown in Table 1. The amino acid and nucleotide sequences ofthe heavy and light chain CDRs of the humanized BAP050 clones are shownin Table 1.

Limited diversity was obtained for the HC FW3 region with eighteenclones having the same FWH3, which is from the human germ line IGHV7-4and has an exposed Cys residue at position 84 of the humanized clones.Closely related VHFW3 sequences typically have a Ser or Ala residue inthis position. Therefore, Cys84 was replaced by Ser in selectedhumanized clones.

FIG. 4 indicates that the samples varied in the concentration of themAb, ranging from 3.2 μg/mL to 35.8 μg/mL. These numbers wererepresentative of several transient expression experiments.

Example 1.4: Analysis of the Humanized Clones Example 1.4.1: Analysis ofBinding Activity and Binding Specificity of Humanized Clones

The binding activity and specificity was measured in a competitionbinding assay using a constant concentration of FITC-labeled murine mAb,serial dilutions of the test mAbs, and LAG-3-expressing CHO cells.Incubations with the mAb mixtures having different concentration ratiosof test mAb to labeled mAb was at 4° C. for 30 min. Bound labeled murinemAb was then quantified using a FACS machine. The experiment wasperformed twice. The results are shown in FIGS. 5A-5B.

Within the accuracy of the experiment, all humanized clones show similaractivity for competing with binding of labeled murine mAb. The activityis also comparable to the activity of the parent murine mAb and chimericmAb. MAbs were ranked relative to each other. For example, it can be aweaker competitor if in both experiments the curve of a certain clone isto the right of the chimeric mAb curve or it can be a better competitorif the curve of a certain clone is to the left of the chimeric mAbcurve. Such a ranking system was used in FIG. 6.

Example 1.4.2: Sequence Analysis of Humanized Clones

Based on structural features, the twenty humanized mAbs were dividedinto six groups and ranked them from A to F. The results are shown inFIG. 6.

Example 1.4.3: Selection of Humanized Clones and Generation of NewVersions with the C84S Mutation

FIG. 6 summarizes the data which was considered for the selection ofhumanized clones. Expression data (2^(nd) column), the diversity in thecomposition of the variable regions (3^(rd) column), relative rankingsin binding studies (4^(th) and 5^(th) columns), and structural analysis(6^(th) column), were considered. Certain characteristics that lead tothe selection of individual clones are marked with grey fields.

Certain clones were mutated at position 84 of VHFW3 from Cys to Ser (seeExample 1.3 above). The new versions are called clones Nos. 1S, 2S, 5S,9S, 11S, 12S, and 13S, and together huBAP050(Ser) clones.

Example 1.4.4: Analysis of Binding Activity and Binding Specificity ofhuBAP050(Ser) Clones

The new versions of the selected clones with the C84S mutation in VHFW3were subject to an analogous competition binding assay as describedunder Example 1.4.1. The experiment included the original humanizedclones with the Cys84 residue, the new humanized clones with the Ser84residue, chimeric mAb and the parent murine mAb. The results are shownin FIG. 7.

All tested variants were comparable to the murine parent mAb in blockingthe binding of labeled murine mAb to LAG-3-expressing CHO cells. Itfollows that the behavior of the new humanized clones with the Ser84residue was not different from the behavior of the original humanizedclones with the Cys84 residue.

Example 1.4.5: Blocking of Binding of LAG-3-Ig to MHC Class II on DaudiCells

LAG-3 binds to MHC class II, therefore the selected huBAP050(Ser) cloneswere tested for their ability to block the binding of soluble LAG-3-Igto Daudi cells (a Burkitt's lymphoma cell line) that express MHC classII. The blocking capacity of the mAbs was evaluated in a competitionbinding assay using a constant concentration of LAG-3-huIgG1 Fc fusionprotein (2 μg/mL), serial dilutions of the mAbs to be tested, and Daudicells. Incubation was at 4° C. for 30 min. Bound ligand fusion proteinwas detected with PE-conjugated F(ab′)2 fragment of goat anti-human IgGwhich doesn't recognize IgG4 mAbs (Southern Biotech 2043-09), and flowcytometry. The results are shown in FIG. 8.

Within the accuracy of the experiments, the seven huBAP050(Ser) clones,chimeric mAb and murine parent mAb demonstrated comparable blockingactivity for LAG-3-Ig.

Example 1.4.6: T Cell Epitope Analysis

Humanized mAbs were analyzed for T cell epitopes using Epibase™. Thealgorithm analyzes each possible peptide (each 10-mer along the proteinadvancing by one amino acid) for binding to HLA class II. It estimatesfree energy of binding (ΔG_(bind)) for each peptide and calculates aputative K_(D) (ΔG_(bind)=RT lnK_(D)). Then peptides are labeled S, M,or N for strong, medium, and non-binders. Threshold values used for thisclassification are different for each allotype.

The data was normalized to a risk score. The overall “risk score” is thesum of all potential epitopes to all tested alleles, weighted by theaffinities of the respective peptides but leaving out all potentialepitopes in germ line sequences (lower value therefor is “better”)

There are roughly three categories of mAbs, derived from a large set ofmAbs of different composition as described below.

Risk score of around 500: fully human mAbs generated from humans,“humanized” mice, and phage libraries (“values below 500 are really goodeven for fully human antibodies”). Humanized mAbs specificallyengineered (even the CDRs) to have a low score are typically in the500-700 risk category.

Risk score around 900: typical CDR-grafted antibodies, which have fullymurine CDRs with or without changes in the FW region (“Gary Queentechnology”); approved CDR-grafted mAbs are basically all in thiscategory.

Risk score around 1500: chimeric mAbs.

The results for selected humanized BAP050 mAbs are:

Clone No. Risk score 01 999 02 1006 05 967 09 998 11 1042 12 1042 13 950

The risk scores of the seven selected humanized clones are in thetypical CDR-grafted mAb category. For example, the human mAb, adalimumab(Humira®), has a score of 654, which is relatively high for human mAbs(at the upper end of the Gaussian curve) but low in comparison to atypical CDR-grafted mAb.

The scores come from the murine CDRs, specifically the Y residues. Theseare acceptable scores for antibodies for cancer treatment. Changing thescore would mean engineering the murine CDRs, specifically removing Yresidues.

Summary and Conclusions

Murine anti-LAG-3 monoclonal antibody, BAP050, was humanized. Thetechnology entails the cloning of the murine CDRs in-frame into anordered library of human germ line variable region frameworks,expressing the library of cloned variable regions as intact IgG4(S228P)humanized mAbs in CHO cells, and selecting clones that bind withcomparable or higher affinity to the target as the parent mAb.Therefore, the murine CDRs were asked to select the best human germ lineframework sequences that preserve their conformations and thus thebinding affinity and specificity of the parent murine mAb. The sequencesand test samples of twenty humanized versions with unique variableregion sequences were obtained, which had also passed a binding testwith LAG-3-transfected CHO cells. Eighteen clones contained the same HCFW3 germ line sequence, which has a rare Cys at position 84. In sevenselected clones, Cys was replaced by Ser creating new mAbs labeledhuBAP050(Ser) clones. These clones were further analyzed for theirbiological functions (e.g., antigen binding and ligand blocking),structural features, and transient expression in CHO cells.

Example 2: Expression of Humanized Anti-LAG-3 Antibody, BAP050

Five humanized clones described in Example 1 were selected forevaluation of expression in Chinese Hamster Ovary (CHO) cells.

Single gene vectors (SGVs) were constructed using Lonza's GS Xceedvectors (IgG4proΔk for heavy chain and Kappa for light chain). The SGVswere amplified and transiently co-transfected into CHOK1SV GS-KO cellsfor expression at a volume of 2.8 L.

Expression cultures were harvested Day 6 post-transfection and clarifiedby centrifugation and sterile filtration. The clarified cell culturesupernatant was purified using one-step Protein A chromatography.Product quality analysis in the form of SE-HPLC, SDS-PAGE, IEF, and LALwas carried out using purified material at a concentration of 1 mg/mlincluding an antibody as a control sample.

Example 2.1: Vector Construction

The sequences of the light and heavy chain variable domain encodingregions were synthesised by GeneArt AG. Light chain variable domainencoding regions were sub-cloned into pXC-Kappa and heavy chain variabledomain encoding regions into pXC-IgG4pro ΔK vectors respectively usingthe N-terminal restriction site Hind III and the C-terminal restrictionsites BsiWI (light chain) and ApaI (heavy chain). Positive clones werescreened by PCR amplification (primers 1053: GCTGACAGACTAACAGACTGTTCC(SEQ ID NO: 288) and 1072: CAAATGTGGTATGGCTGA (SEQ ID NO: 289)) andverified by restriction digest (using a double digest of EcoRI-HF andHindIII-HF) and nucleotide sequencing of the gene of interest.

Example 2.2: DNA Amplification

A single bacterial colony was picked into 15 ml Luria Bertani (LB)medium (LB Broth, Sigma-Aldrich, L7275) containing 50 μg/ml ampicillinand incubated at 37° C. overnight with shaking at 220 rpm. The resultingstarter culture was used to inoculate 1 L Luria Bertani (LB) mediumcontaining 50 μg/ml ampicillin and incubated at 37° C. overnight withshaking at 220 rpm. Vector DNA was isolated using the QIAGEN PlasmidPlus Gigaprep system (QIAGEN, 12991). In all instances, DNAconcentration was measured using a Nanodrop 1000 spectrophotometer(Thermo-Scientific) and adjusted to 1 mg/ml with EB buffer (10 mMTris-C1, pH 8.5). DNA quality for the single gene vectors was assessedby measuring the absorbance ratio A260/A280. This was found to bebetween 1.88 and 1.90.

Example 2.3: Culture of CHOK1SV GS-KO Cells

CHOK1SV GS-KO cells were cultured in CD-CHO media (Invitrogen,10743-029) supplemented with 6 mM glutamine (Invitrogen, 25030-123).Cells were incubated in a shaking incubator at 36.5° C., 5% CO₂, 85%humidity, 140 rpm. Cells were routinely sub-cultured every 3-4 days,seeding at 2×10⁵ cells/ml and were propagated in order to havesufficient cells available for transfection. Cells were discarded bypassage 20.

Example 2.4: Transient Transfections of CHOK1SV GS-KO Cells

Transient transfections were performed using CHOK1SV GS-KO cells whichhad been in culture a minimum two weeks. Cells were sub-cultured 24 hprior to transfection and cell viability was >99% at the time oftransfection.

All transfections were carried out via electroporation using a GenePulse MXCell (Bio-Rad), a plate based system for electroporation. Foreach transfection, viable cells were resuspended in pre-warmed media to2.86×10⁷ cells/ml. 80 μg DNA (1:1 ratio of heavy and light chain SGVs)and 700 μl cell suspension were aliquotted into each cuvette/well. Cellswere electroporated at 300 V, 1300 μF. Transfected cells weretransferred to pre-warmed media in Erlenmeyer flasks and thecuvette/wells rinsed twice with pre-warmed media which was alsotransferred to the flasks. Transfected cell cultures were incubated in ashaking incubator at 36.5° C., 5% CO₂, 85% humidity, 140 rpm for 6 days.Cell viability and viable cell concentrations were measured at the timeof harvest using a Cedex HiRes automated cell counter (Roche).

Example 2.5: Protein A Affinity Chromatography

Cell culture supernatant was harvested and clarified by centrifugationat 2000 rpm for 10 min, then filtered through a 0.22 μm PES membranefilter. Clarified supernatant was purified using a pre-packed 5 mlHiTrap MabSelect SuRE column (GE Healthcare, 11-0034-94) on an AKTApurifier (10 ml/min). The column was equilibrated with 50 mM sodiumphosphate, 125 mM sodium chloride, pH 7.0 (equilibration buffer) for 5column volumes (CVs). After sample loading, the column was washed with 2CVs of equilibration buffer followed by 3 CVs of 50 mM sodium phosphate,1 M sodium chloride pH 7.0 and a repeat wash of 2 CVs of equilibrationbuffer. The Product was then eluted with 10 mM sodium formate, pH 3.5over 5 CVs. Protein containing, eluted fractions were immediately pHadjusted to pH 7.2 and filtered through a 0.2 am filter.

A single protein-containing peak was observed during the elution phase.This peak was shown to contain the mAb, when analyzed by SE-HPLC andSDS-PAGE. Recovered protein yield is shown in Table 5. The clonesexpressed transiently in a range from 21.9 to 29.4 mg/L.

TABLE 5 Summary of yield, titre, monomer content and endotoxin levelsYield* Titre* Monomer Content Endotoxin levels Product (mg) (mg/L) (%)(EU/mg) Clone F 79.1 28.25 95.63 0.22 Clone G 61.3 21.88 95.31 0.15Clone H 76.0 27.13 97.07 0.20 Clone I 82.3 29.38 97.82 0.05 Clone J 64.024.63‡ 96.97 0.27 *Post Protein A purification; ‡from a 2.6 L expressionculture

Example 2.6: SE-HPLC Analysis

Samples of Protein A purified antibodies were analyzed in duplicate bySE-HPLC on an Agilent 1200 series HPLC system, using a Zorbax GF-250 4μm 9.4 mm ID×250 mm column (Agilent). Aliquots of sample at aconcentration of 1 mg/ml were filtered through a 0.2 μm filter prior toinjection. 80 μl aliquots were injected respectively and run at 1 ml/minfor 15 minutes. Soluble aggregate levels were analysed using Chemstation(Agilent) software.

Chromatography profiles with retention time showing the percentage ofthe overall detected peak areas were obtained for the tested antibodiesand a control IgG4 antibody. The products show a single protein peak atapproximately 8.59 to 8.61 min comparable to the human IgG4 antibodycontrol (about 8.64 min) and consistent with a monomeric antibody. Smallamounts (up to about 3-4%) of higher molecular weight impurities,consistent with soluble aggregates, were detected at retention timesaround 7.90 min.

Example 2.7: SDS-PAGE Analysis

Reduced samples were prepared for analysis by mixing with NuPage 4×LDSsample buffer (Invitrogen, NP0007) and NuPage 10× sample reducing agent(Invitrogen, NP0009), and incubated at 70° C., 10 min. For non-reducedsamples, the reducing agent and heat incubation were omitted. Sampleswere electrophoresed on 1.5 mm NuPage 4-12% Bis-Tris Novex pre-cast gels(Invitrogen, NP0335PK2) with NuPage MES SDS running buffer underdenaturing conditions. 10 μl aliquots of SeeBlue Plus 2 pre-stainedmolecular weight standard (Invitrogen, LC5925) and a control IgG4antibody at 1 mg/ml were included on the gel. 1 μl of each sample at 1mg/ml were loaded onto the gel. Once electrophoresed, gels were stainedwith InstantBlue (TripleRed, ISB01L) for 30 min at room temperature.Images of the stained gels were analysed on a BioSpectrum Imaging System(UVP).

The analysis confirmed the presence of the antibody products and goodlevels of purity. Under non-reducing conditions, a predominant proteinband close to 98 kDa was observed comparable with the control IgG4antibody. The control IgG4 antibody and one tested clone display anadditional fainter band corresponding to a heavy plus light chainhalf-antibody at approximately 70 kDa under non-reducing conditions.This is expected for the control antibody. Two bands were observed underreducing conditions consistent with the size of heavy (close to theposition of the 49 kDa marker) and light chains (close to the positionof the 28 kDa marker) and comparable with the bands found for thecontrol IgG4 antibody.

Example 2.8: Iso-Electric Focussing (IEF) Analysis

Non-reduced samples of Protein A purified antibody were electrophoresedas described below.

5 μg of Protein A purified samples were electrophoresed on a 1.0 mmNovex pH 3-10 gradient gel (Invitrogen, EC66552BOX) using manufacturersrecommended running conditions. A 10 μl aliquot of IEF pH 3-10 markers(Invitrogen, 39212-01) was included on the gel. Once electrophoresed,gels were fixed with 10% TCA solution for 30 min and then stained withInstantBlue (TripleRed, ISB01L) over night at room temperature. Imagesof the stained gels were analysed on a BioSpectrum Imaging System (UVP).

As shown in Table 6, the tested clones display charge isoforms betweenpH 6.0 and 7.45. The detected charge isoforms are comparable to thetheoretically calculated pIs for these antibodies which were predictedto be between 6.35 and 6.82. Clones F and G both have a predicted pI of6.35 and show comparable charge isoforms, which is also consistent withthe theoretically calculated pI being the same for both (6.35). Thecontrol IgG4 antibody behaved as expected.

TABLE 6 Charge isoforms as detected by Novex IEF analysis pI ofpredominant Acidic charge Basic charge Product charge isoform* isoforms*isoforms* Clone F 6.2 2x; 6.0 to 6.1 6.3 Clone G 6.2 2x; 6.0 to 6.1 6.3Clone H 7.4 2x; 6.9 to 7.3 7.45 Clone I 7.0 2x; 6.7 to 6.9 7.3 Clone J6.5 2x; 6.0 to 6.4 6.8 *pI readings are estimated from the stainingpositions correlated against the IEF 3-10 marker.

Example 2.9: Endotoxin Analysis

Endotoxin levels of purified proteins were measured at finalconcentrations (up to 3.44 mg/ml) using an Endosafe-PTS instrument, acartridge based method based on the LAL assay (Charles River).

As shown in Table 8, the endotoxin content was found to range from 0.05to 0.27 EU/mg.

Conclusion

GS single gene expression vectors for selected humanized anti-LAG-3 mAbswere constructed and used to transiently transfect CHOK1SV GS-KO cells.2.6 to 2.8 litres of expression culture were incubated under standardconditions for 6 days and the resulting cell culture supernatantpurified using Protein A chromatography. Post-purification litres areindicated in Table 8 and were found to be ranging from 21.88 to 29.38mg/L. The recovered yields range from 61.3 to 82.3 mg.

SDS-PAGE and SE-HPLC analysis indicated the presence of a small amount(up to 4.69%) of soluble aggregates present in the products beingpredominantly consistent with dimeric antibody for the mAb. The mAbsalso showed higher molecular weight impurities at retention timesconsistent with that of trimeric antibodies.

Iso-electric focusing detected a number of charge isoforms for all mAbs.The mAbs showed isoforms generally more basic when based ontheoretically calculated pI for these molecules indicating some level ofpost translation modification. The mAbs were found to be comparable totheir theoretically calculated pI values.

The endotoxin levels for all samples were measured prior to provision ofsamples and found to be below 0.63 EU/mg.

Example 3: Characterization of Murine and Humanized Anti-LAG-3Antibodies Example 3.1: Characterization of Murine Anti-LAG-3 Antibody

The binding affinity of murine anti-LAG-3 antibody BAP050 to LAG-3 wasinvestigated. As shown by FACS analyses, the murine anti-LAG-3 antibodybinds to human LAG-3 transfected CHO cells with a K_(D) of 0.2 nM, tohuman T cells with a K_(D) of 0.26 nM, and to human LAG-3 transfected300.19 cells with a K_(D) of 13.6 nM.

The blocking activity of murine anti-LAG-3 antibody BAP050 was examinedby competition binding assays. The murine anti-LAG-3 antibody blockedLAG-3-Ig binding to MHC class II molecules on Raji cells with an IC50 of2.3 nM.

The effect of murine anti-LAG-3 antibody BAP050 on interferon gamma(IFN-γ) expression was tested. The murine anti-LAG-3 antibody resultedin 3.0±2.1 fold increase in IFN-γ expression on cells stimulated withanti-CD3 (0.1 μg/mL), 1.6±0.4 fold increase on cells stimulated withStaphylococcal enterotoxin B (SEB) (3 pg/mL), and 1.4±0.3 fold increaseon cells stimulated with CMV peptides.

The regions in LAG-3 that may bind murine anti-LAG-3 antibody BAP050were examined. As shown by ELISA, the murine anti-LAG-3 antibody binds aLAG-3 Ig fusion protein (sLAG-3 D1-D4Ig) that contains all fourextracellular Ig-like domains (D1-D4), as well as a LAG-3 Ig fusionprotein (sLAG-3 D1-D2Ig) that only contains Domain 1 (D1) to Domain 2(D2). Further analysis shows that the anti-LAG-3 antibody binds CHOcells that express full length LAG-3, LAG-3 with D2 deletion(CHO-LAG-3AD2), and LAG-3 with partial deletion of D1 extra loop(CHO-LAG-3AP48A60). Thus, the anti-LAG-3 antibody binds D1 of LAG-3.

The murine anti-LAG-3 antibody BAP050 was also found to increase IFN-γsecretion in CD3-stimulated PBMCs compared to mouse IgG control and noantibody control. The fold of increase ranges from 1.4 to 2.9-fold amongfour donors.

Example 3.2: Characterization of Humanized Anti-LAG-3 Antibody BindingAffinity and Specificity

The binding of an exemplary humanized anti-LAG-3 antibody on human LAG-3protein was measured using Biacore method. The results are: Ka=6.41×10⁵M⁻¹s⁻¹; Kd=7.00×10⁻⁵ s⁻¹; K_(D)=0.109±0.008 nM. The anti-LAG-3 antibodyalso binds cynomolgus LAG-3 as measured by Biacore method.

The binding of the same humanized anti-LAG-3 antibody on humanLAG-3-expressing CHO cells and cynomologous monkey LAG-3 expressing HEK209 cells. was measured using FACS analysis. The result shows that theanti-LAG-3 antibody (human IgG4) binds with high affinity to human LAG-3compared to a human IgG4 isotype control. The anti-LAG-3 antibody bindshuman LAG-3-expressing cells with a K_(D) of 1.92 nM and bindscynomologous monkey LAG-3-expressing cells with a K_(D) of 2.3 nM.

The binding of the anti-LAG-3 antibody on rhesus LAG-3-expressing 300.19cells was also measured. The results show that the anti-LAG-3 antibodybinds rhesus LAG-3 with a K_(D) of 8.03 nM.

Additional binding analyses show that the exemplary humanized anti-LAG-3antibody is not cross-reactive with mouse LAG-3 or cross-reactive withparental cell line.

Blocking of Interactions Between LAG-3 and its Ligands

The ability of the exemplary humanized anti-LAG-3 antibody to block theinteractions between LAG-3 and both of its known ligand, MHC class IImolecules, was examined. The results show that the anti-LAG-3 antibodyblocked the interaction between LAG-3 and MHC class II molecules onDaudi cells with an IC50 of 5.5 nM, compared to a human IgG4 isotypecontrol.

LAG-3 Stimulation of Cytokine Release In Vitro in the Absence of T CellReceptor Engagement

Anti-LAG-3 antibody is not expected to stimulate detectable cytokineresponses without specific stimulation by the T cell receptor.Anti-LAG-3 antibody was immobilized and highly crosslinked by air-dryingon a tissue culture plate and tested for its ability to stimulatecytokine production using a method derived from Stebbings R., et al. (JImmunol. 2007 179(5):3325-3331). No IL-2 or IFN-γ production was inducedby anti-LAG-3 antibody or control IgG in the absence of staphylococcalenterotoxin B (SEB) stimulation of whole blood.

Example 4: Patient Selection Based on PD-L1/CD8/IFN-γ Status

For each of several types of cancer, samples from multiple patients weretested for PD-L1/CD8/IFN-γ status. Each sample was classified as:triple-negative for PD-L1/CD8/IFN-γ, single or double positive for thesemarkers, or triple-positive for these markers. FIG. 11 shows that inthis experiment, within a population of patients, the following types ofcancer are frequently triple-positive for PD-L1/CD8/IFN-γ: Lung cancer(squamous), lung cancer (adenocarcinoma), head and neck cancer, cervicalcancer (squamous), stomach cancer, thyroid cancer, melanoma, andnasopharyngeal cancer. Patients having these types of cancer are goodcandidates for therapy with anti PD-1 antibodies in combinationtherapies as described herein, e.g., anti-LAG-3 antibodies. Thelikelihood of successful treatment can be further boosted by determiningwhich patients are triple-positive for PD-L1/CD8/IFN-γ, and treating thetriple-positive patients with anti-PD-1 or anti-PD-L1 antibodies andcombination therapies as described herein, e.g., anti-LAG-3 antibodies.

FIG. 12 shows that within a population of patients, the following typesof cancer are rarely triple positive for PD-L1/CD8/IFN-γ: ER+ breastcancer and pancreatic cancer. Notably, even in cancers that aregenerally not positive for PD-L1/CD8/IFN-γ, one can increase thelikelihood of successful treatment by determining which patients aretriple-positive for PD-L1/CD8/IFN-γ, and treating the triple-positivepatients with anti-PD-1 or anti-PD-L1 antibodies and combinationtherapies as described herein, e.g., anti-LAG-3 antibodies.

FIG. 13 shows the proportion of breast cancer patients that are triplepositive for PDL1/CD8/IFN-γ. Considering breast cancer in general, theproportion of triple-positives is somewhat low. However, when onefocuses only on IM-TN breast cancer, it can be seen that a much largerpercentage of patients is triple positive for PD-L1/CD8/IFN-γ. IM-TNbreast cancer is particularly difficult to treat with conventionaltherapies. The discovery that IM-TN breast cancer is oftentriple-positive for PD-L1/CD8/IFN-γ opens up new avenues of therapy forthis cancer with anti-PD-1 or anti-PD-L1 antibodies and combinationtherapies as described herein, e.g., anti-LAG-3 antibodies.

FIG. 14 shows the proportion of colon cancer patients that are triplepositive for PD-L1/CD8/IFN-γ. Considering colon cancer in general, theproportion of triple-positive is somewhat low. However, when one focusesonly on MSI-high (high microsatellite instability) breast cancer, it canbe seen that a much larger percentage of patients is triple positive forPD-L1/CD8/IFN-γ. MSI levels can be assayed using, e.g., commerciallyavailable PCR-based methods.

Gastric cancer samples were tested for levels of PD-L1/CD8/IFN-γ (datanot shown). It was found that in MSI-high or EBV+ gastric cancers, about49% were positive for PD-L1, and a high proportion of the PD-L-positivecells were triple positive for PD-L1/CD8/IFN-γ. It was also found that aproportion of PD-L-positive cells and PD-L1/CD8/IFN-γ positive cellswere also positive for PIK3CA. This finding suggests that these cancersmay be treated with a PD-1 or an anti-PD-L1 antibody, e.g., incombination with an anti-LAG-3 antibody, optionally in combination witha PIK3 therapeutic.

MSI-high CRC samples were tested for a combination of markers (data notshown). It was found that in MSI-high CRC samples, a high proportion ofthe PD-L1/CD8/IFN-γ samples are also positive for LAG-3, PD-1 (alsocalled PDCD1), RNF43, and BRAF. This finding suggests that these cancersmay be treated with a LAG-3 antibody, optionally in combination with atherapeutic that targets one or more of PD-1, PD-L, PDCD1, RNF43, andBRAF.

Squamous cell lung cancers were tested for a combination of markers(data not shown). It was found that in squamous cell lung cancersamples, a high proportion of the PD-L1/CD8/IFN-γ samples are alsopositive for LAG-3. This finding suggests that these cancers may betreated with a LAG-3 antibody, optionally in combination with atherapeutic that targets PD-1 or PD-L1, e.g., an anti-PD-1 antibody oran anti-PD-L1 antibody.

Papillary thyroid cancers were tested for a combination of markersincluding the BRAF V600E mutation (data not shown). It was found that ahigh proportion of thyroid cancer samples that are positive for PD-L1are also positive for BRAF V600E. This finding suggests that thesecancers may be treated with an anti-PD-1 antibody or an anti-PD-L1antibody, e.g., in combination with an anti-LAG-3 antibody, optionallyin combination with a therapeutic that targets BRAF.

Example 5: Patient Selection Based on PD-L1 Status

To enable broad examination of cancer indications for immunomodulator(e.g., LAG-3 alone or in combination with PD1/PD-L1) based therapies,PD-L1 expression was evaluated at both the protein and mRNA levels inhuman cancers including both lung and hepatic tumors.

PD-L1 protein expression was evaluated in a set of formalin-fixedparaffin-embedded non-small cell lung (NSCLC) adenocarcinoma (ACA),NSCLC squamous cell carcinoma (SCC), and hepatocellular carcinoma (HCC)tumors by immunohistochemistry (IHC). PD-L1 expression was scoredsemi-quantitatively by a manual histo-score (H-score) methodology basedon staining intensity and percentage of positive tumor cells. In our IHCanalysis, PD-L1 positivity (PD-L+) was defined as an H-score ≧20. Inparallel, PD-L1 mRNA expression data was examined from The Cancer GenomeAtlas (TCGA) in these same indications (503 NSCLC ACA, 489 NSCLC SCC,and 191 HCC) and analyzed by comparing the expression in matched normaltissues from TCGA.

With RNAseq analysis, data was calculated as log 2 (RPKM+0.1) after RSEMnormalization, utilizing OmicSoft RNASeq pipelines across TCGA tumorindications. The expression of PD-L1 is elevated in NSCLC ACA and SCC,relative to that in HCC. By overlaying the distributions and comparingthe expression levels across all indications in TCGA, we rankedoverexpression profiles for PD-L1 and found the TCGA HCC cohort to havemuch reduced PD-L1 mRNA levels, with a median level of −0.8 compared to1.3 for ACA and 1.5 for SCC, which amounts to more than a 2-fold changeof median level expression. With RNAseq, our analysis defines 50% ofNSCLC adenocarcinoma, 54% of NSCLC squamous cell carcinoma, and 6% ofHCC as high expressers for PD-L1.

Tumor cell PD-L1 protein expression was measured in 45 lungadenocarcinoma (ACA) samples, 47 lung squamous cell carcinoma (SCC)samples, and 36 hepatocellular carcinoma (HCC) samples. 16/45 (35.6%)lung ACA, 21/47 (44.7%) lung SCC were PD-L1 positive. In contrast, PD-L1positivity was seen in only 2/36 (5.6%) HCC samples.

In summary, with IHC and RNAseq analysis in large and independent humanNSCLC and HCC sample sets, PD-L1 expression was found to be moreenriched in NSCLC than in HCC. Within NSCLC, there are comparablefindings between adenocarcinoma and squamous cell carcinomas.Importantly, amongst the large number of samples (128 for IHC and 1183for RNAseq) in the 3 indications, very good concordance is observedbetween protein- and mRNA-based analyses. This finding thus establishesthe basis for large scale mRNA-based data mining in TCGA for indicationsand patient segments that may be enriched for responses toimmunomodulator (e.g., PD-1/PD-L, e.g., in combination with LAG-3) basedimmune therapies.

INCORPORATION BY REFERENCE

All publications, patents, and Accession numbers mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

What is claimed is:
 1. An isolated antibody molecule capable of bindingto human Lymphocyte Activation Gene-3 (LAG-3), comprising: (a) a heavychain variable region (VH) comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a light chain variable region(VL) comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequenceof SEQ ID NO: 15; (b) a VH comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 aminoacid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ IDNO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 12; (c) a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 286, a VHCDR2amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 15; or (d) a VH comprising a VHCDR1amino acid sequence of SEQ ID NO: 286; a VHCDR2 amino acid sequence ofSEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 aminoacid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQID NO:
 12. 2. The antibody molecule of claim 1, wherein said antibodymolecule is a humanized antibody molecule.
 3. The antibody molecule ofclaim 1, which comprises a heavy chain variable domain comprising theamino acid sequence of SEQ ID NO: 8, 28, 64, 68, 72, 76, 80, 100, 104,or
 108. 4. The antibody molecule of claim 1, which comprises a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92, or
 96. 5. The antibodymolecule of claim 1, which comprises a heavy chain comprising the aminoacid sequence of SEQ ID NO: 18, 30, 66, 70, 74, 78, 82, 102, 106, 110,113, 122, or
 134. 6. The antibody molecule of claim 1, which comprises alight chain comprising the amino acid sequence of SEQ ID NO: 34, 38, 42,46, 50, 54, 58, 62, 86, 90, 94, or
 98. 7. The antibody molecule of claim1, which comprises a heavy chain variable domain and a light chainvariable domain selected from the group consisting of: (a) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 28 orSEQ ID NO: 100; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 32; (b) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 36; (c) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 40; (d)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 28 or SEQ ID NO: 100; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 44; (e) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 28 orSEQ ID NO: 100; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 48; (f) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 52; (g) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 56; (h)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 28 or SEQ ID NO: 100; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 60; (i) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 64 orSEQ ID NO: 104; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 36; (j) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 40; (k) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 56; (l)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 64 or SEQ ID NO: 104; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 60; (m) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 68 orSEQ ID NO: 108; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 36; (n) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 72 or SEQ ID NO: 8; anda light chain variable domain comprising the amino acid sequence of SEQID NO: 40; (o) a heavy chain variable domain comprising the amino acidsequence of SEQ ID NO: 72 or SEQ ID NO: 8; and a light chain variabledomain comprising the amino acid sequence of SEQ ID NO: 60; (p) a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:76 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 60; (q) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 80 and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 84; (r) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 28 orSEQ ID NO: 100; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 88; (s) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 92; and (t) a heavy chain variable domain comprising theamino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:96.
 8. The antibody molecule of claim 1, which comprises a heavy chainand a light chain selected from the group consisting of: (a) a heavychain comprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO:102; and a light chain comprising the amino acid sequence of SEQ ID NO:34; (b) a heavy chain comprising the amino acid sequence of SEQ ID NO:30 or SEQ ID NO: 102; and a light chain comprising the amino acidsequence of SEQ ID NO: 38; (c) a heavy chain comprising the amino acidsequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chaincomprising the amino acid sequence of SEQ ID NO:
 42. (d) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102;and a light chain comprising the amino acid sequence of SEQ ID NO: 46;(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 orSEQ ID NO: 102; and a light chain comprising the amino acid sequence ofSEQ ID NO: 50; (f) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 30 or SEQ ID NO: 102; and a light chain comprising the aminoacid sequence of SEQ ID NO: 54; (g) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chaincomprising the amino acid sequence of SEQ ID NO: 58 (h) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102;and a light chain comprising the amino acid sequence of SEQ ID NO: 62.(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 orSEQ ID NO: 106; and a light chain comprising the amino acid sequence ofSEQ ID NO: 38; (j) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 66 or SEQ ID NO: 106; and a light chain comprising the aminoacid sequence of SEQ ID NO: 42; (k) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chaincomprising the amino acid sequence of SEQ ID NO: 58 (l) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106;and a light chain comprising the amino acid sequence of SEQ ID NO: 62;(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 orSEQ ID NO: 110; and a light chain comprising the amino acid sequence ofSEQ ID NO: 38; (n) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 74 or SEQ ID NO: 18; and a light chain comprising the aminoacid sequence of SEQ ID NO: 42; (o) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 74 or SEQ ID NO: 18; and a light chaincomprising the amino acid sequence of SEQ ID NO: 62; (p) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 78 and a light chaincomprising the amino acid sequence of SEQ ID NO: 62; (q) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 82 and a light chaincomprising the amino acid sequence of SEQ ID NO: 86; (r) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102;and a light chain comprising the amino acid sequence of SEQ ID NO: 94;(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 orSEQ ID NO: 106; and a light chain comprising the amino acid sequence ofSEQ ID NO: 98; (t) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 113 and a light chain comprising the amino acid sequence ofSEQ ID NO: 34; (u) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 113 and a light chain comprising the amino acid sequence ofSEQ ID NO: 38; (v) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 122 and a light chain comprising the amino acid sequence ofSEQ ID NO: 38; (w) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 122 and a light chain comprising the amino acid sequence ofSEQ ID NO: 58; and (x) a heavy chain comprising the amino acid sequenceof SEQ ID NO: 134 and a light chain comprising the amino acid sequenceof SEQ ID NO:
 38. 9. The antibody molecule of claim 1, which is a Fab,F(ab′)2, Fv, or a single chain Fv fragment (scFv).
 10. The antibodymolecule of claim 1, which comprises a heavy chain constant regionselected from IgG1, IgG2, IgG3, and IgG4 and a light chain constantregion chosen from the light chain constant regions of kappa or lambda.11. The antibody molecule of claim 10, which comprises a human IgG4heavy chain constant region with a Serine to Proline mutation atposition 108 of SEQ ID NO: 275 or 277 and a kappa light chain constantregion.
 12. The antibody molecule of claim 10, which comprises one ormore of: (a) a human IgG heavy chain constant region with an Asparagineto Alanine mutation at position 180 of SEQ ID NO: 279 and a kappa lightchain constant region; (b) a human IgG heavy chain constant region withan Aspartate to Alanine mutation at position 148, and Proline to Alaninemutation at position 212 of SEQ ID NO: 280 and a kappa light chainconstant region; or (c) a human IgG heavy chain constant region with aLeucine to Alanine mutation at position 117 and Leucine to Alaninemutation at position 118 of SEQ ID NO: 281 and a kappa light chainconstant region.
 13. The antibody molecule of claim 1, which has one ormore of the following properties: (a) is capable of binding to humanLAG-3 with a dissociation constant (K_(D)) of less than about 0.2 nM;(b) binds an extracellular Ig-like domain of LAG-3; (c) is capable ofreducing binding of LAG-3 to a major histocompatibility (MHC) class IImolecule, or a cell that expresses an MHC class II molecule; or (d) iscapable of enhancing an antigen-specific T cell response.
 14. Abispecific antibody molecule having a first binding specificity forLAG-3 and a second binding specificity for PD-1, TIM-3, CEACAM-1,CEACAM-5, PD-L1 or PD-L2, wherein the bispecific antibody moleculecomprises: (a) a heavy chain variable region (VH) comprising a VHCDR1amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a lightchain variable region (VL) comprising a VLCDR1 amino acid sequence ofSEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and aVLCDR3 amino acid sequence of SEQ ID NO: 15; (b) a VH comprising aVHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequenceof SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and aVL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequenceof SEQ ID NO: 12; (c) a VH comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 286, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and aVHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence ofSEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or (d)a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 286; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO:
 12. 15. The bispecific antibodymolecule of claim 14, wherein said bispecific antibody molecule is ahumanized antibody molecule.
 16. The bispecific antibody molecule ofclaim 14, which comprises a heavy chain variable domain comprising theamino acid sequence of SEQ ID NO: 8, 28, 64, 68, 72, 76, 80, 100, 104,or
 108. 17. The bispecific antibody molecule of claim 14, whichcomprises a light chain variable domain comprising the amino acidsequence of SEQ ID NO: 32, 36, 40, 44, 48, 52, 56, 60, 84, 88, 92, or96.
 18. The bispecific antibody molecule of claim 14, which comprises aheavy chain comprising the amino acid sequence of SEQ ID NO: 18, 30, 66,70, 74, 78, 82, 102, 106, 110, 113, 122, or
 134. 19. The bispecificantibody molecule of claim 14, which comprises a light chain comprisingthe amino acid sequence of SEQ ID NO: 34, 38, 42, 46, 50, 54, 58, 62,86, 90, 94, or
 98. 20. The bispecific antibody molecule of claim 14,which comprises a heavy chain variable domain and a light chain variabledomain selected from the group consisting of: (a) a heavy chain variabledomain comprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO:100; and a light chain variable domain comprising the amino acidsequence of SEQ ID NO: 32; (b) a heavy chain variable domain comprisingthe amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:36; (c) a heavy chain variable domain comprising the amino acid sequenceof SEQ ID NO: 28 or SEQ ID NO: 100; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 40; (d) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 28 orSEQ ID NO: 100; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 44; (e) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 48; (f) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 52; (g)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 28 or SEQ ID NO: 100; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 56; (h) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 28 orSEQ ID NO: 100; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 60; (i) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 64 or SEQ ID NO: 104;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 36; (j) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 64 or SEQ ID NO: 104; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 40; (k)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 64 or SEQ ID NO: 104; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO: 56; (l) a heavy chainvariable domain comprising the amino acid sequence of SEQ ID NO: 64 orSEQ ID NO: 104; and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 60; (m) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 68 or SEQ ID NO: 108;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 36; (n) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 72 or SEQ ID NO: 8; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 40; (o)a heavy chain variable domain comprising the amino acid sequence of SEQID NO: 72 or SEQ ID NO: 8; and a light chain variable domain comprisingthe amino acid sequence of SEQ ID NO: 60; (p) a heavy chain variabledomain comprising the amino acid sequence of SEQ ID NO: 76 and a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:60; (q) a heavy chain variable domain comprising the amino acid sequenceof SEQ ID NO: 80 and a light chain variable domain comprising the aminoacid sequence of SEQ ID NO: 84; (r) a heavy chain variable domaincomprising the amino acid sequence of SEQ ID NO: 28 or SEQ ID NO: 100;and a light chain variable domain comprising the amino acid sequence ofSEQ ID NO: 88; (s) a heavy chain variable domain comprising the aminoacid sequence of SEQ ID NO: 28 or SEQ ID NO: 100; and a light chainvariable domain comprising the amino acid sequence of SEQ ID NO: 92; and(t) a heavy chain variable domain comprising the amino acid sequence ofSEQ ID NO: 64 or SEQ ID NO: 104; and a light chain variable domaincomprising the amino acid sequence of SEQ ID NO:
 96. 21. The bispecificantibody molecule of claim 14, which comprises a heavy chain and a lightchain selected from the group consisting of: (a) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102;and a light chain comprising the amino acid sequence of SEQ ID NO: 34;(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 orSEQ ID NO: 102; and a light chain comprising the amino acid sequence ofSEQ ID NO: 38; (c) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 30 or SEQ ID NO: 102; and a light chain comprising the aminoacid sequence of SEQ ID NO:
 42. (d) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chaincomprising the amino acid sequence of SEQ ID NO: 46; (e) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 30 or SEQ ID NO: 102;and a light chain comprising the amino acid sequence of SEQ ID NO: 50;(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 30 orSEQ ID NO: 102; and a light chain comprising the amino acid sequence ofSEQ ID NO: 54; (g) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 30 or SEQ ID NO: 102; and a light chain comprising the aminoacid sequence of SEQ ID NO: 58 (h) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chaincomprising the amino acid sequence of SEQ ID NO:
 62. (i) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106;and a light chain comprising the amino acid sequence of SEQ ID NO: 38;(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 orSEQ ID NO: 106; and a light chain comprising the amino acid sequence ofSEQ ID NO: 42; (k) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 66 or SEQ ID NO: 106; and a light chain comprising the aminoacid sequence of SEQ ID NO: 58 (l) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 66 or SEQ ID NO: 106; and a light chaincomprising the amino acid sequence of SEQ ID NO: 62; (m) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 70 or SEQ ID NO: 110;and a light chain comprising the amino acid sequence of SEQ ID NO: 38;(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 orSEQ ID NO: 18; and a light chain comprising the amino acid sequence ofSEQ ID NO: 42; (o) a heavy chain comprising the amino acid sequence ofSEQ ID NO: 74 or SEQ ID NO: 18; and a light chain comprising the aminoacid sequence of SEQ ID NO: 62; (p) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 78 and a light chain comprising the aminoacid sequence of SEQ ID NO: 62; (q) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 82 and a light chain comprising the aminoacid sequence of SEQ ID NO: 86; (r) a heavy chain comprising the aminoacid sequence of SEQ ID NO: 30 or SEQ ID NO: 102; and a light chaincomprising the amino acid sequence of SEQ ID NO: 94; (s) a heavy chaincomprising the amino acid sequence of SEQ ID NO: 66 or SEQ ID NO: 106;and a light chain comprising the amino acid sequence of SEQ ID NO: 98;(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 113and a light chain comprising the amino acid sequence of SEQ ID NO: 34;(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 113and a light chain comprising the amino acid sequence of SEQ ID NO: 38;(v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 122and a light chain comprising the amino acid sequence of SEQ ID NO: 38;(w) a heavy chain comprising the amino acid sequence of SEQ ID NO: 122and a light chain comprising the amino acid sequence of SEQ ID NO: 58;and (x) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:38.
 22. The bispecific antibody molecule of claim 14, which is a Fab,F(ab′)2, Fv, or a single chain Fv fragment (scFv).
 23. The bispecificantibody molecule of claim 14, which comprises a heavy chain constantregion selected from IgG1, IgG2, IgG3, and IgG4, and a light chainconstant region chosen from the light chain constant regions of kappa orlambda.
 24. The bispecific antibody molecule of claim 23, whichcomprises a human IgG4 heavy chain constant region with a Serine toProline mutation at position 108 of SEQ ID NO: 275 or 277 and a kappalight chain constant region.
 25. The bispecific antibody molecule ofclaim 23, which comprises one or more of: (a) a human IgG heavy chainconstant region with an Asparagine to Alanine mutation at position 180of SEQ ID NO: 279 and a kappa light chain constant region; (b) a humanIgG heavy chain constant region with an Aspartate to Alanine mutation atposition 148, and Proline to Alanine mutation at position 212 of SEQ IDNO: 280 and a kappa light chain constant region; or (c) a human IgGheavy chain constant region with a Leucine to Alanine mutation atposition 117 and Leucine to Alanine mutation at position 118 of SEQ IDNO: 281 and a kappa light chain constant region.
 26. The bispecificantibody molecule of claim 14, which has one or more of the followingproperties: (a) is capable of binding to human LAG-3 with a dissociationconstant (K_(D)) of less than about 0.2 nM; (b) binds an extracellularIg-like domain of LAG-3; (c) is capable of reducing binding of LAG-3 toa major histocompatibility (MHC) class II molecule, or a cell thatexpresses an MHC class II molecule; or (d) is capable of enhancing anantigen-specific T cell response.
 27. A pharmaceutical compositioncomprising the antibody molecule of claim 1 and a pharmaceuticallyacceptable carrier, excipient or stabilizer.
 28. A pharmaceuticalcomposition comprising the bispecific antibody molecule of claim 14 anda pharmaceutically acceptable carrier, excipient or stabilizer.
 29. Anisolated nucleic acid comprising a first nucleotide sequence thatencodes a VH, or a second nucleotide sequence that encodes a VL, orboth, of an antibody molecule capable of binding to human LAG-3, whereinthe antibody molecule comprises: (a) a heavy chain variable region (VH)comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 aminoacid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQID NO: 3; and a light chain variable region (VL) comprising a VLCDR1amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence ofSEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; (b) aVH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO: 12; (c) a VH comprising a VHCDR1 aminoacid sequence of SEQ ID NO: 286, a VHCDR2 amino acid sequence of SEQ IDNO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 aminoacid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQID NO: 15; or (d) a VH comprising a VHCDR1 amino acid sequence of SEQ IDNO: 286; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 aminoacid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ IDNO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO:
 12. 30. Thenucleic acid molecule of claim 29, wherein the first and the secondnucleotide sequences are in the same nucleic acid molecule.
 31. Thenucleic acid molecule of claim 29, wherein the first and the secondnucleotide sequences are in separate nucleic acid molecules.
 32. Anisolated nucleic acid molecule comprising a first nucleotide sequencethat encodes a VH, or a second nucleotide sequence that encodes a VL, orboth, of a bispecific antibody molecule having a first bindingspecificity for LAG-3 and a second binding specificity for PD-1, TIM-3,CEACAM-1, CEACAM-5, PD-L1 or PD-L2, wherein the bispecific antibodymolecule comprises: (a) a heavy chain variable region (VH) comprising aVHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequenceof SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and alight chain variable region (VL) comprising a VLCDR1 amino acid sequenceof SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and aVLCDR3 amino acid sequence of SEQ ID NO: 15; (b) a VH comprising aVHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequenceof SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and aVL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequenceof SEQ ID NO: 12; (c) a VH comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 286, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and aVHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence ofSEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or (d)a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 286; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO:
 12. 33. The nucleic acid molecule ofclaim 32, wherein the first and the second nucleotide sequences are inthe same nucleic acid molecule.
 34. The nucleic acid molecule of claim32, wherein the first and the second nucleotide sequences are inseparate nucleic acid molecules.
 35. An expression vector comprising thenucleic acid molecule of claim
 29. 36. An expression vector comprisingthe nucleic acid molecule of claim
 32. 37. A host cell comprising thenucleic acid molecule of claim
 29. 38. A host cell comprising thenucleic acid molecule of claim
 32. 39. A method of producing an antibodymolecule, comprising culturing the host cell of claim 37 underconditions suitable for gene expression.
 40. A method of producing anantibody molecule, comprising culturing the host cell of claim 38 underconditions suitable for gene expression.
 41. A method of stimulating animmune response in a subject, comprising administering to a subject inneed thereof an isolated antibody molecule of claim 1 in an amounteffective to stimulate the immune response.
 42. A method of stimulatingan immune response in a subject, comprising administering to a subjectin need thereof a bispecific antibody molecule of claim 14 in an amounteffective to stimulate the immune response.
 43. A method of treating acancer, comprising administering to a subject in need thereof anantibody molecule capable of binding to human LAG-3 in an amounteffective to treat the cancer, wherein the antibody molecule comprises:(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5,and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chainvariable region (VL) comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 15; (b) a VH comprising a VHCDR1 aminoacid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ IDNO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 aminoacid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQID NO: 12; (c) a VH comprising a VHCDR1 amino acid sequence of SEQ IDNO: 286, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 aminoacid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ IDNO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or (d) a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 286; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO:
 12. 44. The method of claim 43,wherein the cancer is chosen from a lung cancer, a melanoma, a renalcancer, a renal cell carcinoma, a liver cancer, a myeloma, a prostatecancer, a breast cancer, a head and neck cancer, a colorectal cancer, apancreatic cancer, a hematological cancer, a non-Hogdkin's lymphoma, ora leukemia, or a metastatic lesion of the cancer.
 45. The method ofclaim 43, wherein the antibody molecule is administered in combinationwith a second therapeutic agent or procedure chosen from one or more ofchemotherapy, a targeted anti-cancer therapy, an oncolytic drug, acytotoxic agent, an immune-based therapy, a cytokine, surgicalprocedure, a radiation procedure, an activator of a costimulatorymolecule, an inhibitor of an inhibitory molecule, a vaccine, or acellular immunotherapy.
 46. The method of claim 45, wherein the antibodymolecule is administered in combination with an agonist of acostimulatory molecule chosen from one or more of OX40, CD2, CD27, CDS,ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30,CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 orCD83 ligand.
 47. The method of claim 45, wherein the antibody moleculeis administered in combination with an inhibitor of an immune checkpointchosen from one or more of PD-1, PD-L1, PD-L2, CTLA4, TIM3, VISTA, BTLA,TIGIT, LAIR1, CD160, 2B4 or TGFR.
 48. A method of treating a cancer,comprising administering to a subject in need thereof a bispecificantibody molecule in an amount effective to treat the cancer, whereinthe bispecific antibody molecule has a first binding specificity forLAG-3 and a second binding specificity for PD-1, TIM3-3, CEACAM-1,CEACAM-5, PD-L1 or PD-L2, and wherein the bispecific antibody moleculecomprises: (a) a heavy chain variable region (VH) comprising a VHCDR1amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a lightchain variable region (VL) comprising a VLCDR1 amino acid sequence ofSEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and aVLCDR3 amino acid sequence of SEQ ID NO: 15; (b) a VH comprising aVHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequenceof SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and aVL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequenceof SEQ ID NO: 12; (c) a VH comprising a VHCDR1 amino acid sequence ofSEQ ID NO: 286, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and aVHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence ofSEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 15; or (d)a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 286; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO:
 12. 49. The method of claim 48,wherein the cancer is chosen from a lung cancer, a melanoma, a renalcancer, a renal cell carcinoma, a liver cancer, a myeloma, a prostatecancer, a breast cancer, a head and neck cancer, a colorectal cancer, apancreatic cancer, a hematological cancer, a non-Hogdkin's lymphoma, ora leukemia, or a metastatic lesion of the cancer.
 50. The method ofclaim 48, wherein the bispecific antibody molecule is administered incombination with a second therapeutic agent or procedure chosen from oneor more of chemotherapy, a targeted anti-cancer therapy, an oncolyticdrug, a cytotoxic agent, an immune-based therapy, a cytokine, surgicalprocedure, a radiation procedure, an activator of a costimulatorymolecule, an inhibitor of an inhibitory molecule, a vaccine, or acellular immunotherapy.
 51. The method of claim 50, wherein thebispecific antibody molecule is administered in combination with anagonist of a costimulatory molecule chosen from one or more of OX40,CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137),GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160,B7-H3 or CD83 ligand.
 52. The method of claim 50, wherein the bispecificantibody molecule is administered in combination with an inhibitor of animmune checkpoint chosen from one or more of PD-1, PD-L1, PD-L2, CTLA4,TIM3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.
 53. A method oftreating an infectious disease, comprising administering to a subject inneed thereof an antibody molecule of claim 1 in an amount effective totreat the infectious disease.
 54. A method of treating an infectiousdisease, comprising administering to a subject in need thereof thebispecific antibody molecule of claim 14 in an amount effective to treatthe infectious disease.
 55. A method of detecting LAG-3 in a biologicalsample, comprising (i) contacting the sample or the subject with anisolated antibody molecule of claim 1 under conditions that allowinteraction of the antibody molecule and the polypeptide to occur, and(ii) detecting formation of a complex between the antibody molecule andthe sample or the subject (and optionally, the reference sample orsubject).